Advice to reduce dietary salt intake is a key element of many lifestyle intervention programs for type 2 diabetes. However, the association between dietary salt intake and mortality outcomes has not been previously studied specifically in the context of type 2 diabetes. In this article, we show that 24hUNa was independently associated with all-cause and cardiovascular mortality in patients with type 2 diabetes such that the highest mortality risks were observed in individuals with the lowest sodium intake and vice versa.
Although such data may seem contrary to established dogma, in fact previous observational studies, both in the general population and in hypertensive patients, have failed to give consistent results regarding the association of salt and mortality. In some studies, higher salt intake has been associated with an increased risk of cardiovascular events (12
), while in others—including the National Health and Nutrition Examination Surveys (NHANES) I, II, and III—lower salt intake has been associated with an increased risk of cardiovascular events and or mortality (16
). Other studies in the general community have failed to demonstrate any association of dietary salt intake with cardiovascular events (18
). Although hypertension and CVD are common in patients with type 2 diabetes, the issue of whether dietary salt intake influences mortality and morbidity has not been studied specifically in the context of type 2 diabetes, and any inference from outcomes in other populations should be viewed with caution.
The major strength of the current study is the use of multiple 24-h urine collections to estimate dietary sodium intake. With few exceptions (13
), the majority of previous studies that have examined the association between salt and mortality, including NHANES (17
), have relied on dietary recall, which can underestimate dietary salt intake by up to half (21
). All patients were trained in urine collection and were experienced in performing 24-h urine collections at the start of the study. Moreover, in this population, the annual intraindividual CV of 24hUNa
was low (23% over an 8-year period). In addition, the urinary sodium excretion observed was very similar to previous global population surveys (11
), confirming that the patients were not sodium-restricted, which may otherwise confound analysis by indication.
The chief limitations of our data are that they are context-specific. The findings of our study specifically detail outcomes in a high-risk subpopulation of patients with longstanding type 2 diabetes attending a tertiary referral center. Nonetheless, these are precisely the patients in whom more aggressive lifestyle interventions are often applied. Our patients were mostly obese, hypertensive, with a history of poor metabolic control, and multiple comorbidities, including a significant burden of renal impairment and preexisting CVD at baseline. In all patients, cardiac risk factors were treated aggressively. It is possible that in this clinical setting, nontraditional risk factors have a stronger relationship with outcomes or that paradoxical associations are observed (22
). For example, most of our patients were hypertensive despite treatment, and it has been previously shown in treated hypertensive men that low 24hUNa
is associated with an increased risk of cardiovascular morbidity and mortality (16
) and that tight blood pressure control in diabetic patients is associated with increased all-cause mortality (23
). However, in our study, the relationship between urinary sodium excretion and mortality was independent of the presence and severity of hypertension.
In our statistical analysis, we specifically assessed the nonlinear effects of predictive variables modeled for potential interactions and, in the case of cardiovascular mortality, modeled within the paradigm of a formal competing risks (Fine and Gray) model, which estimated the cumulative incidence of cardiovascular deaths while taking into consideration the competing risk of other causes of death, which may otherwise confound results (24
). This strategy is especially important in patients with diabetes, as diabetes is also associated with increased noncardiovascular mortality (25
), which may potentially confound cause-specific analysis. Although such strategies have a number of advantages, it is nevertheless possible that associations demonstrated in this study may be because of confounding by unmeasured factors or those that are difficult to quantify. Variability in dietary sodium intake may be associated with a range of differences in diet composition, processing, and preparation that may themselves impact on adverse outcomes in diabetic individuals. For example, sodium intake is dominated by sodium added in manufactured foods in Western diets, (~75% of intake) (11
). In addition, we cannot exclude the possibility that salt appetite and cardiovascular risk are linked to a common unidentified etiological factor.
Any pathophysiological mechanisms that may underlie our observed association between mortality and salt intake in patients with type 2 diabetes remain to be established. Certainly, RAAS activity (4
), insulin resistance (5
), catecholamine levels (4
), and lipids (4
) may be influenced by sodium intake, and each of these potential mediators may be of particular relevance in the setting of type 2 diabetes and/or established atherosclerosis. For example, dietary sodium restriction leads to increased levels of angiotensin II and aldosterone, chiefly via an increase in plasma renin activity. Given the primacy of RAAS in the development and progression of diabetes complications, as adjudged by the efficacy of RAAS blockade, it is perhaps not surprising that activation of RAAS by reducing sodium intake may also be associated with adverse outcomes. The same may also be said for increased sympathetic activity, insulin resistance, and dyslipidemia associated with sodium restriction.
In summary, we show that 24hUNa
, the best marker of dietary sodium intake, was negatively associated with all-cause mortality specifically in the setting of type 2 diabetes, after adjusting for baseline risk factors. This may reflect the special status of dietary salt and the pathways it regulates in diabetic pathophysiology. Such data call into question universal recommendations that all adults should endeavor to reduce their salt intake (12
). Ultimately, the explanation for our findings needs to be tested experimentally in clinical trials performed specifically in diabetic patients.