We thank Lambers Heerspink et al. (1) for their comments and agree that observational studies are prone to confounding. We also agree that our study population represents high-risk patients with advanced type 2 diabetes and does not represent the general population. Importantly, after adjusting for factors independently associated with all-cause mortality including age, sex, duration of diabetes, atrial fibrillation, the presence and severity of chronic kidney disease (estimated glomerular filtration rate and log albumin excretion rate), and parameters associated with 24-h urinary sodium excretion (24hUNa) including BMI, all-cause mortality remained inversely associated with 24hUNa such that individuals with a lower 24hUNa had a higher cumulative hazard for mortality. Furthermore, the mean systolic blood pressure (sBP) in each tertile of 24hUNa was very similar, i.e., 141 ± 17 mmHg (Tertile 1, 24hUNa <150 mmol); 140 ± 17 mmHg (Tertile 2, 24hUNa:150–208 mmol); and 140 ± 16 mmHg (Tertile 3, 24hUNa >208 mmol). These levels approximate mean achieved sBP in the control groups of two recent studies in high-risk patients with type 2 diabetes. Neither cardiovascular events in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (2) nor total mortality in the International Verapamil-Trandolapril (INVEST) study (3) were reduced by intensive blood pressure control.
Lambers Heerspink et al. also question whether the renin-angiotensin system could be activated in the range of 24hUNa reported in our study. In a subgroup of patients drawn from the same population reported in our study, we have previously shown that habitual low dietary salt intake (24hUNa:118 ± 12 mmol) is associated with a significantly increased plasma renin activity when compared with a habitual high dietary salt intake group (24hUNa:271 ± 24 mmol) (4). Furthermore, high plasma renin activity was an independent predictor of major vascular events and mortality in the Heart Outcomes Prevention Evaluation (HOPE) study (5).
We have also previously shown favorable short-term effects of a low salt diet on blood pressure and albuminuria in patients with type 2 diabetes (4). However, the recent long-term study in patients with type 1 diabetes has shown that there is a steep increase in mortality when urinary sodium excretion is <100 mmol/24 h, and there is an inverse relationship between 24hUNa and the incidence of end-stage renal disease (6).
In support of our data, a recently published community-based longitudinal study (7) has shown that despite sBP being aligned with changes in 24hUNa, this did not translate into higher risk of cardiovascular disease end points. Lower 24hUNa was associated with higher cardiovascular disease mortality.
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