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New diagnostics for hypertension in diabetes and the role of chronotherapy: a new perspective

Rossen, Niklas B.; Hansen, Klavs W.

Cardiovascular Endocrinology & Metabolism: December 2016 - Volume 5 - Issue 4 - p 144–150
doi: 10.1097/XCE.0000000000000103
Review Articles
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Globally, diabetes has become one of the major causes of premature morbidity and mortality, and this is mainly attributable to the increased risk of cardiovascular (CV) disease. CV risk stratification is based on well-established risk factors including hypertension, diabetes, dyslipidaemia, smoking, age and sex. However, current assessment models are imperfect. Improved risk stratification may be achieved by the use of home and ambulatory blood pressure (BP) monitoring. Identification of new CV risk factors, which add prognostic information, may also improve risk stratification. Pulse wave velocity and central BP have been suggested as new parameters with independent prognostic ability. Moreover, treatment targets of hypertension are not met in many patients. Strategies to improve BP control include new ways of drug treatment, with chronotherapy offering a cost-free and simple approach. The present paper will review these issues with a specific focus on studies in diabetic patients.

aDepartment of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus

bDiagnostics Centre, Silkeborg Regional Hospital, Silkeborg, Denmark

Correspondence to Niklas B. Rossen, MD, PhD, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Tage-Hansens Gade 1, DK-8000 Aarhus C, Denmark Tel: +45 78467745; fax: +45 78467749; e-mail: niklas.rossen@rm.dk

Received September 1, 2016

Accepted September 20, 2016

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Introduction

Globally, diabetes has become one of the major causes of premature morbidity and mortality, and this is mainly attributable to the increased risk of cardiovascular (CV) disease. In the last decades, advances in primary and secondary prevention of CV disease have resulted in considerable reductions in the rate of incident CV events in diabetic patients. However, CV disease is still responsible for 50–80% of deaths in individuals with diabetes, and diabetes confers a two-fold excess risk for fatal and nonfatal CV disease 1,2.

CV risk stratification is based on well-established risk factors including hypertension, diabetes, dyslipidaemia, smoking, age and sex. However, current assessment models are imperfect as individuals with apparently equal risk have varying degrees of CV risk. Thus, the current uniform treatment strategies may lead to insufficient treatment of individuals with very high risk and excessive treatment of low-risk individuals.

Improved stratification may be achieved by the attainment of more valid measurements of blood pressure (BP) as well as measurements yielding information on diurnal variations in BP. In this respect, the use of home and ambulatory blood pressure monitoring (ABPM) is central.

Identification of new CV risk factors, which add prognostic information, may also improve risk stratification. Pulse wave velocity (PWV) and central BP have been suggested as new parameters with independent prognostic ability.

Finally, treatment targets of hypertension are not met in many patients. Strategies to improve BP control include new ways of drug treatment, with chronotherapy offering a cost-free and simple approach.

The present paper will review these issues, with a specific focus on studies in diabetic patients.

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New diagnostics

Ambulatory blood pressure monitoring

For decades, office BP has been the gold standard for BP measurement. However, in recent years, the importance of ABPM in the management of hypertension has been established 3, and ABPM is now recommended for the diagnosis and evaluation of treatment in the latest hypertension guidelines 4,5. ABPM has not only been proven to be superior to office BP in terms of reproducibility 6, but it has also shown superiority in the prediction of CV events in patients with hypertension 7–10 and in the general population 11–16.

The predictive ability of ABPM has also been established in diabetic patients. In a study by Eguchi et al.17, 301 patients with type 2 diabetes were followed up for 50±23 months. Although office systolic blood pressure (SBP) was found to predict CV risk, only 24-h BP remained a significant predictor in multivariable Cox regression analysis.

In patients with diabetes, ABPM is particularly important. Night-time BP has been shown to be superior to daytime BP in the prediction of CV events (see below) and nocturnal hypertension is expected to be more prevalent in diabetic patients because of their accumulation of factors involved in the development of nocturnal hypertension. Thus, the diagnosis of nocturnal hypertension as well as the evaluation of therapeutic strategies to reduce night-time BP make ABPM pivotal in BP control in diabetic patients.

In this issue of Cardiovascular Endocrinology, the office BP targets in diabetes have been discussed. Currently, no internationally accepted ABPM targets exist for high-risk patients, including diabetic patients.

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Home blood pressure monitoring

The use of ABPM is challenged in some parts of the world by being a more expensive measurement technique. Moreover, some individuals find the measurement uncomfortable to a degree, where they prefer not to have it performed. These challenges are in part met by the increasing use of home BP monitoring. Only a few prospective studies are available, but it seems that home BP is superior to office BP in the prediction of CV events 18 and even similar to the predictive ability of daytime ambulatory blood pressure (ABP) 19.

Several studies have shown that home BP monitoring is feasible in achieving BP control in patients with diabetes 20,21, and a good correlation between home BP and daytime ABP has also been established 22,23. To our knowledge, no studies have specifically evaluated the predictive role of home BP in relation to CV events in patients with diabetes. However, the ability to predict the progression of nephropathy has been shown in several studies, implying a potential role in the prediction of CV events in diabetic patients 24,25.

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Pulse wave velocity and central blood pressure

The risk of CV disease is estimated by assessment of nonmodifiable risk factors, for example, age and sex, and modifiable risk factors including hypertension, dyslipidaemia, diabetes and smoking. However, individual risk assessment is challenged by the fact that the modifiable CV risk factors fluctuate over time and evaluation of traditional CV risk factors represents only a snapshot of the individuals’ CV risk profile. Thus, the cumulative impact on the vascular system from the longitudinal exposure of the risk factors is not necessarily reflected.

To improve the current risk stratification, it is important to identify new CV risk factors, which add prognostic information and reflect the accumulated damage from longitudinal risk exposure.

PWV, the gold-standard method for assessing arterial stiffness, has been suggested as a new risk factor with independent prognostic ability for CV disease and total mortality 26,27. Indeed, in a large meta-analysis, it was found to be a strong predictor of future CV events and all-cause mortality 28. When added to conventional risk factors, PWV has been shown to improve clinical risk assessment 29,30. In patients with diabetes, PWV has also been shown to provide CV risk prediction independent of standard risk factors as well as improvement of risk stratification 31,32.

Central BP, an index of central haemodynamics, has also been suggested as an independent CV risk factor, but so far, solid evidence has not been provided. In contrast, Laugesen and colleagues just published the largest study to date on this issue 33. In 21 908 patients with stable angina pectoris undergoing elective coronary angiography, office SBP and invasively measured aortic SBP were recorded. Using The Danish Registry of Patients and The Danish Civil Registration System, data on admissions for myocardial infarction and stroke as well as all-cause mortality were retrieved. After a median follow-up of 3.7 years, the predictive ability of aortic SBP for the risk of myocardial infarction, stroke and all-cause mortality was found not to exceed that of office SBP. Moreover, no evidence was found for aortic SBP to improve discrimination and reclassification beyond office SBP. These conclusions applied to patients both with and without diabetes.

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Chronotherapy

BP shows a circadian rhythm with lower values during sleep than during wakefulness. The BP rhythm is affected by extrinsic factors, such as physical activity, behavioural and lifestyle factors, and sleep quality, and by intrinsic factors, that is, neurohormonal regulation 34.

In recent years, focus on night-time BP has increased as several studies have found night-time SBP to be superior to daytime SBP in the prediction of CV events in patients referred for ABPM 35, in patients with hypertension 8,10 as well as in the general population 12,13. Meta-analyses of studies in hypertensive patients and general populations have reached the same conclusions 36–38. The predictive role of night-time BP has also been established in diabetic patients 39–41.

Chronotherapy is the concept of optimizing drug treatment, that is, increasing desired effects and reducing side effects, by determining the most efficient time of drug administration in relation to known biological rhythms. The concept has been known for many years 42 and it is applied in many clinical situations, for example, statin and insulin treatment. The impact of chronotherapy on night-time BP may be particularly important because of the superior predictive role of night-time BP over daytime BP.

Bedtime administration of once-daily antihypertensive drugs is a chronotherapeutic approach, which has been investigated in relation to BP as well as intermediate and hard endpoints.

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Studies on blood pressure

Bedtime administration of different classes of antihypertensive drugs has been shown to reduce night-time BP, although the results are not unequivocal. The effects on daytime and 24-h BP with bedtime administration are variable. Tables 1 and 2 summarize the results of the most important randomized-controlled trials on the BP effects of morning versus bedtime administration of antihypertensive drugs in monotherapy.

Table 1

Table 1

Table 2

Table 2

A 2011 Cochrane review evaluated the administration time-related effects of antihypertensive drugs administered as once-daily monotherapy on all-cause mortality, CV morbidity and mortality (primary outcome) and reduction of BP and adverse effects (secondary outcome) 61. None of the randomized-controlled trials, which fulfilled the inclusion criteria of the review, reported on the primary outcome. Compared with morning dosing, 24-h BP was significantly lower with bedtime administration. The review did not report on differences in daytime nor night-time BP. No differences in adverse events or withdrawals because of adverse events were found. The overall conclusion was that bedtime administration was superior to morning administration in achieving better BP control.

Only a few prospective trials have investigated the effects of bedtime administration of multiple antihypertensive drugs. The study designs, methods and populations, the investigated drug classes and combinations, and the BP effects show considerable heterogeneity and do not allow for unequivocal conclusions 62–68. However, at the European Society of Hypertension 2016 in Paris, data from the as yet unpublished HARMONY study by Poulter et al.69 were presented. In a randomized cross-over study with 103 patients treated with more than one antihypertensive drug, no difference in 24-h SBP was found between morning and evening dosing. Interestingly, although not significant, a reduction in night-time SBP of 1.68 mmHg was found with evening dosing. The authors speculated that this reduction could be important at the population level in relation to reducing CV events.

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Studies on intermediate endpoints

An association between night-time BP and urinary albumin excretion and development of chronic kidney disease has been found in several studies 70–72, including among patients with diabetes 73–80. In randomized-controlled trials with varying prevalence of diabetic patients, bedtime administration of antihypertensive drugs has been shown to reduce urinary albumin excretion 55,62,81,82.

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Studies on cardiovascular risk

At present, indications of improved prognosis with bedtime administration of antihypertensive drugs have primarily originated from studies not specifically designed to investigate the effects of chronotherapy on CV risk.

In the HOPE study, ramipril was found to significantly reduce CV morbidity and mortality as well as the development of overt nephropathy in patients with diabetes 83. According to the study protocol, treatment (ramipril and placebo) was administered at bedtime. The CV benefit was greater than that attributable to the decrease in office BP. A HOPE substudy evaluated ABPM data of 38 patients and found a nonsignificant reduction in office BP and ambulatory daytime BP, but a significant reduction in 24-h BP, mainly because of a highly significant reduction in night-time BP 84. Thus, it was suggested that the beneficial effects found in the HOPE study to a larger extent were related to the effects on BP over the 24-h period and that these effects were related to the administration of ramipril at bedtime.

In ASCOT-BPLA, the antihypertensive treatment regimen of amlodipine–perindopril was associated with beneficial effects on almost all CV outcomes compared with a regimen of atenolol–thiazide 85. Both treatment regimens were administered in the morning. Only about half of the between-treatment differences were explained by multivariate adjustments for postrandomization differences in CV risk factors. The ABP substudy of ASCOT found that the amlodipine–perindopril and atenolol–thiazide regimens had different effects on daytime and night-time BP 86. In the amlodipine–perindopril group, daytime BP was higher and night-time BP was lower. It was suggested that the lower night-time BP may have contributed towards the lower event rates with the amlodipine–perindopril regimen.

The MAPEC study is the only trial on the chronotherapeutic effects of antihypertensive drugs on CV risk 87. A total of 2156 hypertensive patients were randomized to take all of their antihypertensive drugs in the morning or one or more at bedtime. After a median follow-up of 5.6 years, the group taking one or more antihypertensive drugs at bedtime not only had significantly lower night-time BP but also a significantly lower relative risk of CV events.

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Studies in diabetic patients

Data on the effects of chronotherapy of antihypertensive drugs in diabetes come primarily from three studies.

Tofé Povedano et al.46 carried out an open-label cross-over study with olmesartan in 38 type 2 diabetic patients. A significant reduction of 4.3 mmHg in night-time SBP was found with bedtime administration, with no significant differences in daytime or 24-h SBP.

From the MAPEC study population, Hermida et al.88 carried out a subgroup analysis on 448 patients with type 2 diabetes. Bedtime administration of one or more antihypertensive drugs resulted in a significant reduction in night-time SBP of 7.4 mmHg, with nonsignificant reductions in daytime and 48-h BP. After a median follow-up of 5.4 years, it was found that bedtime administration of one or more antihypertensive drugs resulted in a significantly lower CV risk. A highly unexpected and somewhat provocative finding from a recent analysis of the MAPEC population was the prevention of new-onset diabetes in patients administered one or more antihypertensive drugs at bedtime 89.

Our research group carried out an open-label cross-over study in 41 patients with type 2 diabetes and nocturnal hypertension (night-time SBP≥120/70 mmHg) 90. In our study, we changed the time of administration of all of the individual’s once-daily antihypertensive drugs (median n=3). We found that bedtime administration not only significantly reduced night-time SBP with 7.5 mmHg but also 24-h SBP with 3.1 mmHg, the latter finding being novel.

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The future of chronotherapy

A recent systematic review by Schillaci et al.91 found that bedtime administration of antihypertensive drugs was associated with a sizeable reduction in night-time BP as well as a modest, although significant, reduction in mean 24-h BP. However, these findings were subject to considerable between-centre heterogeneity. After excluding the results of a single centre, which accounted for about 50% of the participants, the reduction in 24-h BP disappeared. The MAPEC study, which originates from the mentioned centre, has also been criticized for having methodological weaknesses and some of the conclusions have also been questioned 92.

However, more recent studies not originating from the mentioned centre have yielded interesting results. Although not a significant reduction, the effect on night-time SBP found in the HARMONY study may, as suggested by the authors, have clinical implications. In this respect, the studies by Tofé Povedano and colleagues and Rossen and colleagues 46,90 are important and even more so with respect to the effects of chronotherapy of antihypertensive drugs in diabetic patients.

In our view, chronotherapy is a promising, simple and cost-free approach to a highly relevant and important clinical challenge. We speculate, however, that the benefit of chronotherapy may be most pronounced in, or may even be limited to, patients with increased night-time BP. Moreover, several questions remain unanswered. First, the uncertainty in the change of administration time of some or all antihypertensive drugs needs clarification. Second, although the present data do not point to a safety concern of a chronotherapeutic intervention, this should be documented in vulnerable subgroups such as very old patients or patients with ischaemic heart disease. Third, more light needs to be shed on the mechanisms responsible for the chronotherapeutic effects on BP. The need for undisputable evidence showing that bedtime administration of antihypertensive drugs transforms into a reduction in CV risk is pivotal. Hopefully, some of these questions will be answered by ongoing studies 93,94. However, because of study designs, they may not answer the question of specific benefits in patients with increased night-time BP.

Whereas the continued implementation of ABPM is challenged in some parts of the world by being a more expensive measurement technique, the use of chronotherapy may prove to be an important treatment strategy to reduce healthcare costs. If well-designed and well-executed, large-scale studies confirm the effects of bedtime administration on not only night-time BP but also 24-h BP, a chronotherapeutic approach may be a valuable instrument to improve hypertension treatment without increasing costs. This benefit is global but, of course, even more significant in low-income parts of the world with limited healthcare resources.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

ambulatory blood pressure monitoring; cardiovascular risk; central blood pressure; chronotherapy; diabetes; home blood pressure monitoring; hypertension; pulse wave velocity

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