SUMMARY
Twenty-four–hour ambulatory blood pressure monitoring (ABPM) is a method widely used
in hypertension diagnosis and management. Also in diabetic subjects, it may be a powerful
tool for a better stratification of cardiovascular risk related to elevated blood
pressure (BP), one of the most important causes of morbidity and mortality in this
population. This is due to its capacity, as compared with isolated office measurements,
to more precisely diagnose and quantify a high BP condition in daily life and to detect
alterations of 24-h BP profiles such as absence of nocturnal BP fall, postprandial
hypotension, or an increased BP variability, which may reflect a deranged cardiovascular
regulation often associated with a reduced heart rate variability. It is also an important
tool to obtain an accurate assessment of the efficacy of antihypertensive treatment
over day and night. Admittedly, this method has its disadvantages, which include relatively
high cost, problems with validation of the devices (particularly relevant in special
populations such as diabetic patients), and undefined diagnostic threshold in high-risk
populations. A number of studies have shown that ABPM may be a useful tool in improving
outcome and quality of life in diabetes, suggesting that it should be an integral
part of the clinical management in this setting. However, due to its limited availability
in clinical practice, it may not be easily applied in every diabetic subject and thus
priority should be given to those of diabetic patients, who may derive the most evident
benefits from the use of this diagnostic tool.
INTRODUCTION
The 24-h ABPM is a method widely used in hypertension diagnosis and management (1
–3). Numerous studies over the years have confirmed its advantages over the traditional
clinic measurement, including a higher reproducibility, lack of placebo and white
coat effect, and, most importantly, its superiority in predicting adverse consequences
of hypertension. Additionally, ABPM provides an insight into the features of 24-h
BP variability, which cannot be assessed with either clinic or home BP measurement
(1
–3).
An accurate diagnosis of hypertension and a reliable assessment of its control are
of uppermost importance in high-risk subjects, in whom each mmHg of BP reduction translates
into an important reduction of hypertension-related morbidity and mortality (1,4).
Diabetes is widely recognized to be a condition leading to an important elevation
of cardiovascular risk in combination with hypertension, this being relevant both
in individual patients and in terms of public health. Indeed, missed hypertension
diagnosis or inadequate control of BP levels in diabetic subjects are common (5).
A number of diagnostic and therapeutic tools are available to improve this situation,
and ABPM is one of them. Interestingly, the usefulness of ABPM in diabetes is related
not only to the possibility of assessing the features of BP elevation over 24 h, but
also to its ability to identify BP patterns reflecting an important pathophysiological
mechanism underlying the cardiovascular effects of diabetes, namely autonomic dysfunction.
This article is aimed at discussing the evidence supporting use of ABPM in patients
with diabetes and, based on this evidence, at suggesting the possible clinical indications
for ABPM in individual diabetic patients.
EVIDENCE ON ABPM USEFULNESS IN DIABETES
All the methodological advantages of ABPM, compared with conventional isolated office
BP readings, are fully evident in diabetic subjects, in whom this method, which is
operator independent, offers important information related to the large number of
BP readings provided, to its ability to offer insight into 24-h BP profiles (including
nighttime and morning BP values) and to the possibility to quantify BP variability
over the whole 24-h period (2,3). Some studies have shown that reproducibility of
BP values in diabetic subjects is probably better with ABPM than with clinic BP (6).
Moreover, other favorable features of ABPM, previously demonstrated in uncomplicated
hypertensive subjects, also characterize its application in the diagnostic and therapeutic
management of diabetic subjects with hypertension. These include the absence of a
white-coat effect (i.e., the increase in BP triggered by an emotional reaction to
its measurement in the physician's office) and of a placebo effect when assessing
response to antihypertensive treatment (2,3).
The above methodological advantages were clearly shown to importantly contribute to
the higher predictive value of ABPM in the prognostic stratification of hypertensive
patients. Similarly, as in a nondiabetic population, out-of-office BP values obtained
through ABPM in patients with diabetes were found to correlate better than office
BP with organ (in particular renal) damage (7,8) and cardiovascular events (9).
WHITE-COAT AND MASKED HYPERTENSION
An important issue related to the parallel use of office and out-of-office BP measurement
methods (the latter including also home BP monitoring) in the same subjects when diagnosing
hypertension or when assessing its coverage by treatment should be mentioned in this
context. It has been reported that, in a significant proportion of subjects, major
differences occur in the definition of BP levels obtained with these different approaches
to BP measurement. In a general population, the diagnosis of hypertension based on
elevated office BP values is not confirmed by out-of-office measurements in >20% of
subjects, in whom normal values are found at home or over the 24 h (a condition defined
as white-coat hypertension) (10,11). Conversely, in another 10–20% of subjects, the
opposite situation is found, namely, an elevation in daily life BP identified by either
ABPM or home BP monitoring remains undiagnosed during the clinic or office visit (a
condition indicated as masked hypertension) (11). The prognostic significance of white-coat
hypertension is uncertain, with these subjects probably being at an intermediate risk
level between normotensives and sustained hypertensives (10,11). On the other hand,
a number of studies have consistently shown that masked hypertension is associated
with an elevated cardiovascular risk, similar to that of sustained hypertension (11).
The data on white-coat hypertension and masked hypertension in diabetic subjects are
rather limited. The available information is largely in line with the data obtained
in nondiabetic subjects, although some differences should be underlined. There is
evidence, for instance, that the prevalence of white-coat hypertension in this population
may be lower than in a general population, in particular, when subjects with diabetic
nephropathy are concerned (12). This should not be surprising given that these subjects
tend to have sustained and marked BP elevation, whereas white-coat hypertension is
most common in subjects with BP close to the threshold for hypertension diagnosis.
On the other hand, it was suggested that masked hypertension may be present in one
out of two subjects with type 2 diabetes and apparently normal clinic BP (13). High
prevalence of masked hypertension becomes particularly relevant when we consider that
this condition may be associated with higher risk of brain and kidney damage (14,15)
and possibly also of cardiac damage (13), which further increases the already very
high risk of cardiovascular complications typical of diabetic subjects. As far as
white-coat hypertension is concerned, it appears to be associated with a lower risk
than sustained hypertension also in a diabetic population (16).
ASSESSMENT OF 24-h BP PROFILES
One application of ABPM in diabetic subjects that has raised particular interest is
the possibility to detect the alterations of day-night BP changes that often characterize
such a pathological condition. Specifically, a lack of nocturnal BP fall (nondipping)
or even an increase of BP during the night (reverse dipping) is common in this population,
with its prevalence reaching ∼30% (17,18) (Fig. 1). It was suggested that these conditions
may reflect autonomic dysfunction (19), and some authors suggest that they might be
used as a clinical marker of diabetic autonomic neuropathy (20). However, it has to
be remembered that other pathophysiological mechanisms may also be involved. In particular,
obstructive sleep apnea, commonly encountered in obese subjects with type 2 diabetes
(21), is a condition frequently associated with the nondipping pattern (22).
Figure 1
Size of nocturnal BP fall (dipping) in children with diabetes (■) compared with healthy
control subjects (□). DBP, diastolic BP; SBP, systolic BP. Reprinted with permission
from Dost et al. (18).
Whatever its mechanisms might be, a flattening and, even more importantly, an inversion
of day-night BP profile (reverse dipping) was demonstrated to be a marker of complications
in the diabetic population (17). In particular, its association with renal damage
reflected by urinary protein excretion is evident both in type 1 (23) and type 2 (24)
diabetes. The results of some studies suggest that in subjects with type 1 diabetes,
elevated systolic BP during sleep precedes the development of microalbuminuria. Such
an alteration in nocturnal BP, therefore, should be viewed as a cause (or at least
a marker) of renal damage rather than its consequence (25). More recently, similar
results were obtained also in type 2 diabetes (26). Nondipping in diabetic subjects
may also be associated with an increased overall mortality, but evidence is limited
in this regard (27).
In the context of daytime and nighttime BP assessment by ABPM, one has to consider
the possibility that the absolute values of nocturnal BP might be more relevant from
the prognostic point of view than the relative reduction of day-night BP excursion.
This possibility has been recently supported by the results of a number of outcome
studies in uncomplicated hypertensive subjects, and some data in this direction have
been collected also in subjects with type 2 diabetes (28).
OVERALL BP VARIABILITY AND MORNING BP SURGE
Apart from day-night BP changes, ABPM is able to provide information on other features
of BP variability that may be of interest in diabetic subjects and have clinical relevance.
One of them is the overall BP variability, commonly expressed as a standard deviation
of average 24-h, daytime, or night-time BP values. This parameter is frequently increased
in diabetic subjects, which may be a sign of deranged autonomic control of circulation
and/or of an increased arterial stiffness. This appears to be the case in patients
with diabetic autonomic neuropathy (29), in particular, when associated with arterial
baroreflex impairment (30,31), and may be an independent predictor of cardiovascular
complications (32). Autonomic neuropathy is also frequently associated with postprandial
hypotension, another specific component of 24-h BP variability, which can also be
detected by ABPM (33).
Another important feature of 24-h BP profile is the behavior of BP in the morning.
Both excessive morning BP surge (i.e., the extent of BP increase when waking up in
the morning) and morning hypertension (high BP level in morning hours) are associated
with adverse prognosis in nondiabetic subjects (3). Morning hypertension is common
in diabetic patients, and it was shown to predict the progression rate of diabetic
nephropathy (34). Although in the studies published so far in diabetic patients, home
BP monitoring was applied for the assessment of morning BP behavior, ABPM might be
even better in this regard, since it allows a dynamic and more detailed evaluation
of BP in the morning hours.
ADDITIONAL PARAMETERS DERIVED FROM 24-H ABPM
Another advantage of ABPM is that it allows to obtain dynamic information over 24
h not only on systolic and diastolic BP values, but also on some other relevant parameters
that can be directly obtained or calculated from ambulatory BP recordings. This technique
provides information on heart rate at the time of BP measurements all over the 24
h, and a rough estimate of heart rate variability may also be obtained by computing
the standard deviation of average 24-h, daytime, or nighttime heart rate values. Although
a reduced heart rate variability in continuous ECG recordings is a well established
index of diabetic neuropathy, only one study assessed heart rate variability from
ambulatory BP recordings in diabetic subjects. This study confirmed that the degree
of heart rate fluctuations also when assessed discontinuously over 24 h by means of
intermittent readings is reduced in this population, especially at night (35).
Pulse pressure, i.e., the difference between systolic and diastolic BP, depends on
both stroke volume and arterial properties and, when increased, is largely considered
a surrogate marker of stiffening of arterial walls. Results of several studies indicate
that 24-h pulse pressure may be an independent predictor of vascular complications
of diabetes, more powerful than the assessment of pulse pressure in clinic measurements,
although it is not clear whether it provides relevant additional information on top
of what is already offered by 24-h systolic BP (36) (Fig. 2). In the context of noninvasive
methods for evaluating arterial properties, a new index has been recently proposed,
based on analysis of ABPM data, known as ambulatory arterial stiffness index. This
index consists of the dynamic evaluation of the degree of parallelism in systolic
and diastolic BP changes and is calculated as the regression coefficient between the
changes in diastolic and systolic BP over 24 h. It has been suggested that ambulatory
arterial stiffness index may indirectly reflect the degree of arterial stiffness,
and some studies have demonstrated a relationship of ambulatory arterial stiffness
index with cardiovascular events and organ damage (37). The precise interpretation
of its value as a specific index of arterial stiffness is, however, made difficult
by the evidence of a strong correlation between ambulatory arterial stiffness index
and the degree of nocturnal BP fall (38), a parameter largely independent from arterial
wall properties. Considering that nocturnal BP fall is commonly small or absent in
diabetic subjects, it is hardly surprising that ambulatory arterial stiffness index
scored worse than 24-h pulse pressure in predicting the progression of renal damage
in this population (39).
Figure 2
The rates of occurrences of cardiovascular, cerebrovascular, and all events in diabetic
subjects divided by quartile of the distribution of mean 24-h pulse pressure and by
age at entry (≥40 and 41–59 years). Reprinted with permission from Nakano et al. (36).
DIABETES AND PREGNANCY
Pregnancy is a condition where the interplay between diabetes and hypertension is
of particular importance, since both these conditions adversely influence the pregnancy
outcomes. The role of ABPM in this setting is not well established, however. On one
side, some studies suggest its possible usefulness in monitoring pregnant women and
in the early identification of pregnancy-induced hypertension, especially when nocturnal
BP is considered (40). On the other side, according to some authors, ABPM adds little
information to that already provided by microalbuminuria assessment as far as prediction
of preeclampsia is considered (41).
ABPM IN THE ASSESSMENT OF ANTIHYPERTENSIVE TREATMENT
An extremely important application of ABPM in hypertension is related to its ability
to evaluate the changes in BP induced by antihypertensive therapy with greater accuracy
and in a much more detailed fashion than clinic BP measurements, offering information
on actual 24-h BP coverage by a given antihypertensive regimen (3). Considering that
adequate BP control is of utmost importance in diabetic subjects, the above properties
of ABPM make it an essential tool to verify the appropriateness and efficacy of antihypertensive
treatment also in this group. The key aspects related to ABPM application in this
context include the following: the possibility to identify subjects inappropriately
categorized by clinic BP as controlled (masked hypertension) or uncontrolled (white-coat
hypertension); the ability of ABPM to assess the impact of treatment on particularly
important periods within 24 h (nighttime, morning); and the availability of ABPM-based
indexes of adequate duration of antihypertensive effect (trough-to-peak ratio) and
of the smoothness of BP reduction by treatment throughout 24 h (smoothness index).
In fact, the studies making use of ABPM in diabetic subjects to assess the effects
of hypertension treatment have provided some interesting information. In particular,
evidence has been obtained that newer oral antidiabetic drugs used in type 2 diabetes
(but not the older ones), in particular the thiazolidinediones, may have a beneficial
effect on 24-h BP levels and may also improve the day-night BP profile in diabetic
(42,43) subjects.
Some information is available also on the influence of currently used antihypertensive
regimens on 24-h BP in diabetic patients, including angiotensin receptor antagonists
(44) and ACE inhibitors (45,46). These studies have confirmed the efficacy of these
compounds in terms of overall 24-h BP lowering, with no significant impact on day-night
BP profile. Information has also been obtained by ABPM on the effects of lipophylic
calcium-channel blockers on 24-h BP in diabetic patients. These drugs reduced systolic
BP variability, monitored on a beat-by-beat basis over 24 h, in diabetic patients
with hypertension. This improvement in hemodynamic conditions was associated with
an improved autonomic cardiac modulation, as quantified by an increased cardiac baroreflex
sensitivity (47).
Importantly, the ability of ABPM to provide more precise information on BP control
by treatment might translate into a better clinical practice, through identification
of subjects with white-coat hypertension and masked hypertension and by stimulating
a more aggressive treatment when this is necessary to achieve therapeutic targets
(48).
LIMITATIONS OF ABPM USE IN DIABETES
Although the usefulness of ABPM in diabetic subjects can hardly be questioned, one
also has to consider a few limitations of this technique, which may be important when
ABPM is to be applied in a clinical setting in the management of diabetic patients.
One of the main concerns when applying oscillometric devices in clinical practice
(and current ABPM devices are almost exclusively based on oscillometric measurements)
is that the algorithms for BP determination by these techniques are not disclosed
by manufacturers. Therefore, the validity of each oscillometric device should by individually
checked by independent studies following predefined international protocols. Unfortunately
in diabetic patients, the difference between BP values obtained with the reference
auscultatory measurement and with the oscillometric method is not necessarily the
same found in nondiabetic subjects (49). Therefore, devices with demonstrated validity
in standard protocols carried out in nondiabetic subjects may not necessarily turn
out to be accurate in subjects with diabetes, possibly because of the altered arterial
wall properties typical of such a condition. Thus, ideally, validation studies on
oscillometric devices to be used in diabetic patients should be separately performed
in this population. Unfortunately, whereas many ABPM devices have been validated in
a general hypertensive population, similar studies are lacking in the setting of diabetes.
Nevertheless, considering the prognostic superiority of ABPM over clinic BP measurement
demonstrated also in diabetic patients, the possibility of a minor inconsistency between
auscultatory measurements and oscillometric ABPM values, due to the particular characteristics
of these subjects, should not be viewed as a major obstacle in their clinical application.
An obstacle that is clearly more important from the practical point of view is the
high cost and limited availability of ABPM systems in general practice. Still, this
situation is changing, with the costs of devices becoming lower, the number of centers
equipped with the devices increasing, and the reimbursement policies becoming more
favorable. For the time being, in most developed countries, an access to ABPM for
a high-risk patient, such as one with diabetes, should no longer pose a major difficulty,
also in relation to its reimbursement by health insurance bodies.
Finally, an important but still unresolved issue is the definition of ABPM cutoffs
for hypertension diagnosis and the identification of therapeutic targets in diabetic
subjects. Such thresholds are fairly well defined for nondiabetic subjects at low
or intermediate risk. Based on the results of outcome studies, it is believed that
a clinic BP of 140/90 mmHg corresponds to ambulatory BP levels of 125–130/80 mmHg
for 24 h, 135/85 for daytime, and 120/70 for nighttime (1,2). Conversely, no corresponding
definitions are available when considering high-risk patients such as those with diabetes.
However, given that in this population clinic BP threshold for hypertension diagnosis
and treatment is currently set at values as low as 130/80 mmHg, it should be expected
that also ABPM thresholds should be lower by ∼5–10 mmHg compared with a nondiabetic
population. Given the nonlinearity of the relation between clinic and ambulatory BP,
however, ABPM thresholds in diabetic patients need to be defined on the basis of future
outcome studies.
CONCLUSIONS: INDICATIONS FOR ABPM IN DIABETIC SUBJECTS
In summary, ABPM in diabetic subjects may be a powerful tool for a better stratification
of the cardiovascular risk related to elevated BP, a condition that is one of the
most important causes of morbidity and mortality in this population. This is of particular
importance also on the background of the evidence that, in diabetic patients, office
BP frequently fails to identify their exposure to elevated BP in daily life conditions.
Moreover, ABPM may also be helpful in detecting alterations in autonomic control of
the cardiovascular system, reflected by the absence of nocturnal BP fall, by postprandial
hypotension, or by a reduced 24-h heart rate variability and an increased 24-h BP
variability. Thus, theoretically, a noninvasive and powerful test such as ABPM could
be useful in every diabetic subject.
However, given the limited availability of ABPM in daily practice and the progressive
increase in the number of diabetic subjects, it is reasonable to suggest an individualized
approach when defining indications to ABPM performance in such a population. As a
general principle, ABPM should be applied in those cases where the largest benefits
can be expected. In practice, the pros and cons of performing ABPM should be evaluated
on a case-by-case basis, taking into consideration a number of key factors, such as
the likelihood of misdiagnosing actual BP levels by office BP, the possible benefits
associated with a more accurate estimation of 2-h BP levels and variability (as in
patients with previous clinical events, such as stroke, myocardial infarction, or
impaired renal function), the probability of nocturnal hypertension, and the availability
of alternative (and cheaper) solutions for out-of-office BP measurement, such as home
BP monitoring.
Based on the above considerations, a few recommendations can be proposed to identify
the possible situations in which ABPM might be indicated in hypertensive subjects
with diabetes. One such possibility is the finding of clinic BP values close to the
threshold levels. This is because these patients are most likely to have white-coat
hypertension (if office BP is slightly above the threshold) or masked hypertension
(when it is slightly below). In such a case, however, home BP monitoring may be an
easier, cheaper, and equally effective (50) way to determine the true status of patients'
BP under daily life conditions. When home BP monitoring is not feasible, or its results
are not easy to interpret (borderline values, high variability), ABPM should then
be performed. Another example of subjects in whom a suspicion of imprecise diagnosis
by office BP should be considered are those with signs of organ damage despite apparently
normal BP in the physician's office or in the clinic (in diabetic subjects, it is
much less likely that the opposite situation is encountered). This may imply that
BP is elevated only in their daily life, a condition that needs out-of-office BP monitoring
to be identified. Needless to say, such diabetic patients, being exposed at a very
high risk, may derive particular benefit from an appropriate diagnosis and an effective
treatment of their daily life hypertension.
ABPM may also be of particular importance in subjects already under antihypertensive
treatment. Even though home BP monitoring may be sufficient for a long-term follow-up,
ABPM is the only way to ascertain that BP is adequately controlled all over the 24-h
period and in particular during the night. Nocturnal hypertension should be suspected
specifically in subjects likely to have obstructive sleep apneas (obese subjects,
snoring history, daytime somnolence), in those with autonomic dysfunction, and in
those with organ damage, especially when kidneys are affected (microalbuminuria or
overt proteinuria, signs of renal failure). In these cases, some simple measures,
such as switching to long-acting compounds or adding an evening dose of antihypertensive
drugs, may be effective. However, it should be emphasized in this context that the
occurrence of clinical benefits from restoring a normal day-night BP rhythm is only
assumed and has not yet been directly demonstrated. ABPM may also help to identify
subjects with episodic BP drops (as in the case of postprandial hypotension related
to autonomic dysfunction) and should be performed if patient reports typical hypotensive
symptoms that have not been otherwise clarified. Also in such cases, the adjustment
of antihypertensive treatment or advice on changes in lifestyle may be effective and
improve the subject's quality of life. Finally, ABPM may also be useful when identifying
patients with episodic BP elevations, in the context of an enhanced BP variability,
increased arterial stiffness, and autonomic neuropathy. The identification of these
phenomena may trigger appropriate changes in treatment strategies, too, given the
prognostic relevance of these findings.
In spite of its advantages, ABPM may not be easily applied in every diabetic subject,
both for technical and financial reasons. However, it is important to emphasize that,
when appropriately used, this approach may be an extremely useful tool in improving
outcome and quality of life of these subjects and therefore should become an integral
part of the clinical management, at least in a subgroup of selected diabetic patients.