In this prospective observational study with a follow-up period of 9.5 years, high 24 h PP and impaired nocturnal diastolic blood pressure decline were both strong and independent predictors of nephropathy progression, thus confirming hypotheses generated from previous cross-sectional and short-term observational studies. In the proportional hazards analysis, a 1 mmHg increase in 24 h PP and a 1% increase in diastolic night:day BP ratio conferred an increased risk of nephropathy progression of 4 and 5%, respectively, whereas smoking more than doubled the risk of nephropathy progression, even after adjustment for multiple other potential risk factors.
During the last decade, numerous studies have established PP as a strong, independent predictor of cardiovascular morbidity and mortality in non-diabetic patients [25–30]. In 2002, we published baseline data from the middle-aged Danish type 2 diabetic patients participating in the present follow-up study . In this cross-sectional study, we were the first to demonstrate strong associations between ambulatory PP values and micro- and macrovascular complications; in particular, the association between PP and albuminuria was very strong . Although the cross-sectional design did not allow any firm conclusions regarding causality, we hypothesised that PP could be a risk factor for the progression of albuminuria in this patient group. Subsequently, several studies have associated an elevated PP with both micro- [3, 5] and macrovascular [6–8] complications in diabetic patients.
In 2006, Palmas et al. published a very significant longitudinal study including 1,040 elderly type 2 diabetic patients followed for 12 to 24 months . In that study, 164 of 954 patients without macroalbuminuria at baseline progressed at least one level from normo- or microalbuminuria to micro- or macroalbuminuria. After adjustment for other clinical covariates, ambulatory PP was a strong and independent predictor of albuminuria progression, above and beyond office BP. The study had considerable statistical power, due to a large number of participants and the employment of 24 h AMBP, whereas its limitations included the relatively short follow-up period of only 1 to 2 years, considering the fact that diabetic nephropathy typically evolves over a decade or more . Moreover, albuminuria status was evaluated on the basis of a single urine sample, even though three samples are usually recommended due to the considerable intra-individual day-to-day variability of this key variable . Finally, these important results from elderly participants (mean age around 71 years) cannot necessarily be extrapolated to other age groups with less arterial stiffness and, consequently, a less pronounced elevation of PP. In the present study, we confirm the results from the Palmas study and extrapolate them to a group of middle-aged (mean age 58 years) type 2 diabetic patients followed for 9.5 years with a more precise assessment of nephropathy status (based on three urine samples per patient at baseline as well as at follow-up).
Numerous previous studies have established the superiority of 24 h AMBP over conventional office BP measurement for the association with [1, 5, 15, 32, 33] and prediction of hypertensive end-organ damage in diabetes [9, 34, 35]. Moran et al. found that office and 24 h systolic AMBP were independently associated with albuminuria in elderly type 2 diabetic patients ; however in the longitudinal study mentioned above , ambulatory PP predicted progression of albuminuria above and beyond office BP. In the present study, none of the office BP values had any significant predictive value for the progression of nephropathy, whereas 24 h systolic AMBP and PP values were strong predictors of nephropathy progression in type 2 diabetic patients. Obviously, the shortcomings of office BP measurement in the present study can be ascribed to lack of power, but it is striking that this commonly used diagnostic modality had no predictive value in a 9.5 year follow-up study in a high-risk group of type 2 diabetic patients. These results suggest that more widespread use of 24 h AMBP measurements could significantly improve our ability to identify patients at increased risk of developing microvascular complications.
In addition, use of 24 h AMBP as opposed to office BP measurement provides the opportunity to study diurnal BP fluctuations. In particular, focus has been directed towards a blunted nocturnal BP reduction (‘non-dipping’), a pattern that has been consistently associated with diabetic vascular complications in previous studies [1, 10–17, 35]. In a 3 year follow-up of the same elderly type 2 diabetic patients mentioned above [4, 9], the investigators found that patients with a reversed diurnal BP rhythm (nocturnal BP ‘risers’) had an increased risk of nephropathy progression compared with patients with a normal reduction in BP during night-time (‘dippers’), whereas patients with a reduced nocturnal BP decline (‘non-dippers’) had an intermediate risk of progression . Nocturnal BP rising was an independent predictor of albuminuria progression in the multivariate analysis, whereas non-dipping did not independently predict albuminuria progression. In the present study, we found that a reduced diastolic nocturnal BP decline was an independent predictor of nephropathy progression; moreover, we found a strong and intriguing additive effect of combining diastolic night:day BP ratio and 24 h PP. Thus, in the group of patients with diastolic night:day BP ratio and 24 h PP below the median, only one of 33 patients progressed, whereas 17 of 32 patients in the group with these BP variables equal to or above the median progressed to a more advanced nephropathy stage.
Several questions remain unanswered.
First, what are the underlying pathophysiological mechanisms connecting the haemodynamic abnormalities, elevated PP and blunted nocturnal BP decline, with the development of microvascular complications, in casu progression of nephropathy in type 2 diabetes? We have previously demonstrated strong associations between endothelial perturbation and both non-dipping  and elevated PP , suggesting that an enhanced level of endothelial cell activation could represent a link between these haemodynamic abnormalities and the development of microvascular complications in type 2 diabetes, possibly by promoting inflammation and atherosclerosis and by increasing the tendency of blood clotting. However, we were unable to make firm conclusions regarding causality due to the cross-sectional design of the studies.
Second, could pharmacological intervention against elevated PP or reduced nocturnal BP decline lead to a reduced incidence of microvascular complications? We have recently demonstrated that 12 months dual blockade with an angiotensin 2 receptor antagonist (candesartan) and an ACE inhibitor (lisinopril) was more effective in lowering 24 h ambulatory PP than monotherapy with high-dose lisinopril in type 2 diabetic patients . However, it is as yet unknown whether this narrowing of PP induced by dual blockade of the renin–angiotensin system will translate into a long-term reduction in microvascular complications. Several researchers have demonstrated that it is possible to restore the normal circadian BP pattern in ‘non-dipper’s with selective antihypertensive therapy directed towards an elevated night BP [37–40]. Interestingly, this approach has been reported to reduce 24 h albumin excretion rate in microalbuminuric patients with essential hypertension, thus suggesting an increased organoprotective effect of re-establishing the normal diurnal BP rhythm . These results are interesting and promising, but long-term intervention studies are needed to resolve whether antihypertensive treatment should be directed towards restoring the normal diurnal BP variation in ‘non-dipping’ patients and reducing an elevated PP.
The strengths of the present study include the long follow-up period of 9.5 years, the precise assessment of nephropathy status at baseline and follow-up, as well as the employment of 24 h AMBP measurement. There are several limitations to this study. First, the study was a clinically based observational study; hence, all types of pharmacological intervention were allowed during the follow-up period. Indeed, most patients received additional pharmacological (antihypertensive, lipid-lowering, antithrombotic etc.) therapy during this period, and we do not have the possibility to statistically correct for this intercurrent medication. However, during the follow-up period patients with high baseline BP levels would have been more likely to receive intensified antihypertensive therapy (including ACE inhibitors and angiotensin 2 receptor antagonists) than patients with low BP levels at baseline, thus reducing their risk of nephropathy progression and introducing a bias towards the null hypothesis. In spite of these pharmacological interventions during follow-up, high 24 h PP and reduced diastolic night BP decline were strong predictors of nephropathy progression, suggesting that these variables are useful for risk assessment in everyday clinical practice. Second, the number of patients participating in the study was limited, thus limiting statistical power. As previously discussed, this could explain the lack of predictive value of office BP variables for nephropathy progression in the present study, whereas the very significant results for smoking, 24 h ambulatory PP and diastolic night:day BP ratio despite the limited size of the study indicate that these variables are strong and important predictors of this serious complication.
In the present 9.5 year observational study, 24 h ambulatory PP, impaired nocturnal diastolic BP decline and smoking were strong, independent predictors of nephropathy progression in type 2 diabetic patients. These potentially modifiable risk factors could represent important targets for pharmacological and non-pharmacological intervention aiming at reducing the incidence of this serious complication of type 2 diabetes.