Pulse pressure does not predict the response of diabetic nephropathy to glucose-lowering therapy

Abstract

We aimed to study whether pulse pressure (PP) predicts the response of diabetic nephropathy to glucose-lowering treatment. Patients with uncontrolled type 2 diabetes were followed for decrease in albuminuria after insulin/oral-hypoglycemic treatment. A total of 143 patients were followed for a median time of 10.5 months in a cohort study. Fasting blood sugar and HbA1C significantly decreased, while systolic, diastolic and pulse pressures remained constant during intervention. Median albuminuria decreased from 18.4 mg/day [10–40] to 16.4 mg/day [9–28] at the end of study (p-value < 0.005). The number of patients with normo/micro/macro-albuminuria changed from 98/36/9 to 108/31/4 (p-value < 0.001). No significant difference in baseline PP (47.5 ±1.61 vs. 45.9 ±1.81 mmHg; p-value = 0.51) or final PP (47.0 ±2.41 vs. 49.4 ±2.38 mmHg; p-value = 0.47) existed between those with decreased and increased albuminuria. PP was not a significant predictor of albuminuria changes in receiver operating characteristic curve (p-value = 0.77) and regression (p-value = 0.98) analyses. Benefits of glycemic control in diabetic nephropathy are independent of PP.

Albuminuria is a risk factor for cardiovascular disease in patients with diabetes mellitus. This risk increases paralleled with the degree of albuminuria, starting well below the cut-point definition of microalbuminuria. ¹ Even patients with high-normal urinary albumin excretion rate (UAER; at the range of 20–30 mg/day) show accelerated decline in glomerular filtration rate and are at higher risk of incidence of cardiovascular events, compared with patients with UAER below 20 mg/day. ²

Pulse pressure (PP), a surrogate measure of arterial stiffness and pulsatile flow, is associated with microalbuminuria. ³ It may be more predictive than systolic blood pressure (SBP) and is independent of mean pressure, which is a surrogate measure of steady flow. ³ In prospective studies, wide ambulatory PP was an independent predictor of progression of albuminuria in patients with type 2 diabetes mellitus (T2DM). ⁴ However, it is unclear whether patients with wide PPs are also more resistant to treatment or not. This study aimed to investigate whether PP can predict the response of diabetic nephropathy to glucose-lowering treatment.

Patients with uncontrolled T2DM were recruited from an outpatient diabetes clinic. T2DM was diagnosed according to American Diabetes Association (ADA) ⁵ criteria, and HbA_1c > 7% was required for uncontrolled diabetes. Patients were treated in a standard glucose-lowering therapeutic programme in compliance with ADA guideline. This study complied with the principles of the Declaration of Helsinki. Local ethics review committee approved the study protocol. Demographic and anthropometric data were recorded at baseline. After 10 min of resting, brachial blood pressure was measured in sitting position, in right arm, with manual mercury sphygmomanometer and was re-measured after 5 min and averaged. PP was calculated as the difference between SBP and diastolic blood pressure (DBP). Fasting blood samples were taken after 12 h of overnight fasting at baseline and on follow-up, and a routine metabolic screening was done. Patients were instructed in a timed 24-h urine collection for the measurement of UAER. Normoalbuminuria, microalbuminuria and macroalbuminuria were defined as UAER <30, 30–300 and >300 mg/24 h, respectively.

Continuous variables are presented as mean ± standard error of the mean (SEM) or median (interquartile range). Categorical variables are presented as number and percent. Chi-square, independent and paired sample t-tests were used for group comparisons as indicated. The McNemar test was used for follow-up comparisons of albuminuria. Receiver operating characteristic (ROC) curve analysis was used for cut-point evaluation. Linear and logistic regression analyses were used for data modelling.

A total of 143 patients were followed up for a median time of 10.5 months (6–17.7 months). Study population included 89 females and 54 males, with mean age of 57.9 ± 1.7 years, body mass index (BMI) of 28.8 ± 1.05 kg/m² and diabetes duration of 8.2 ± 0.7 years. A total of 16 patients went on insulin (11%), and oral hypoglycaemic drug (metformin, glibenclamide or combination therapy) was prescribed for others. Fasting blood sugar (FBS) decreased from 160.2 ± 7.9 to 144.8 ± 5.4 mg/dL (p < 0.01). HbA_1c decreased from 8.07% ± 0.21% (65 ± 3 mmol/mol) to 7.05% ± 0.17% (58 ± 2 mmol/mol) (p < 0.005), while lipid profile or creatinine did not change.

A total of 92 patients (64.3%) were using at least one anti-hypertensive drug and 74 patients (51.7%) were using angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) (no association was found between using ACEI/ARB and PP). No new anti-hypertensive drug was prescribed during the study. Mean SBP and DBP were 118.9 ± 1.58 and 71.8 ± 0.92 mmHg at baseline and 117 ± 2.22 and 68.8 ± 1.40 mmHg at end, respectively. Mean PP was 46.8 ± 1.2 mmHg at baseline and 48.1 ± 1.65 mmHg at end. There were no significant changes in SBP, DBP or PP during the study. Median albuminuria decreased from 18.4 (10–40) to 16.4 mg/day (9–28) (p < 0.005). The number of patients with normo-/micro-/macroalbuminuria was 98/36/9 at baseline and 108/31/4 after intervention (p < 0.001).

There was no significant difference at baseline (47.5 ± 1.61 vs 45.9 ± 1.81 mmHg; p = 0.51) or at end (47.0 ± 2.41 vs 49.4 ± 2.38 mmHg; p = 0.47) in PP between patients with decreased and increased albuminuria. ROC curve analysis revealed no significant ability for baseline PP in predicting changes of albuminuria [area under curve (AUC) = 0.51 ± 0.049; p = 0.77].

In linear regression, baseline PP was not a significant predictor of changes in albuminuria (beta: −0.018 ± 0.439; R² = 0.001; p = 0.98). In logistic regression, baseline PP was not a significant predictor of increasing/decreasing direction of albuminuria during intervention [odds ratio = 0.99 (0.96–1.01); p = 0.51].

Both glycaemic and haemodynamic variables play important roles in the development of albuminuria. Control of blood glucose constitutes a mainstay of treatment in patients with diabetic nephropathy. In addition, both SBP and PP are associated with altered renal haemodynamics and have already been proved to predict the natural history of albuminuria. ⁴ Renal resistive index, a marker of renal haemodynamic flow, is strongly correlated with aortic PP, and both are associated with UAER. ⁶

During glucose-lowering intervention, all indices of blood pressure remained relatively constant, and no new anti-hypertensive drug was prescribed. Significant decrease in FBS and HbA_1c revealed glycaemic control in our previously uncontrolled diabetic patients. However, decrease in albuminuria was independent of baseline PP. Even in patients with wide PP, a comparable decrease in UAER was observed after glycaemic control.

Mean SBP and DBP of our participants were below therapeutic cut-points. Considering their poor glycaemic control, haemodynamic factors may be less significant as the aetiology of albuminuria in our study population. About half of the patients were on ACEI/ARB prior to intervention, meaning that glomerular pressure may have already been decreased, even in the presence of a wide PP (although ACEI/ARB usage was not different between patients with low and high PPs). As a conclusion, benefits of glycaemic control are independent of PP in patients with diabetic nephropathy.