Many guidelines recommend and advocate that patients with type 1 diabetes should aim to restrict their dietary intake of salt (1
). Such recommendations have been inferred from data showing that a reduced sodium intake can result in a modest short-term fall in blood pressure in some (but not all) patients with type 1 diabetes (17
). However, the epidemiological associations between sodium intake and long-term outcomes have not been previously explored specifically in patients with type 1 diabetes. Small studies have suggested an association between dietary sodium intake with proliferative retinopathy (18
) and albuminuria in type 1 diabetes (19
). However, this is the first study to show that dietary sodium intake is associated with all-cause mortality in patients with type 1 diabetes and correlated with the development of ESRD in patients with macroalbuminuria, after adjusting for baseline risk factors. Importantly, this association appears to be nonlinear, with an increased risk of death and ESRD in individuals with low sodium excretion, as well as reduced survival in those with high sodium intakes.
That both high and low sodium intake may be associated with adverse mortality outcomes is consistent with epidemiological data from nondiabetic individuals. For example, in the Finnish general population, a high sodium intake has been associated with an increased risk of mortality (14
). In so far as two-thirds of our patients with type 1 diabetes are free of CKD and hypertension, and these complications-free individuals have an age-sex standardized mortality rate not significantly different from that of the general population (7
), similar predictors of mortality may also be anticipated. At the same time, a negative association between sodium intake and mortality has been also observed in hypertensive men (20
) and in aggressively treated patients with type 2 diabetes (21
). It is possible to speculate that the balance of diabetic patients enrolled in our study, which included both healthy individuals and others with established complications, reflects one or other pole, thus cumulatively generating a U-shaped association between salt excretion and mortality. However, the shape of this association was consistent across all subgroups, including those individuals with or without established renal or cardiovascular complications (Supplementary Table 2
), suggesting that other factors are also involved.
Strengths of our study include its very large cohort of individuals with type 1 diabetes, high participation rate, access to subsidized care (75–100% of costs), and contemporary treatment regimens, including a range of insulin regimens, statins, blockers of the RAS, and self-monitoring technologies. We used validated methods to identify deaths, and all deaths in our cohort were confirmed through death records. Surveillance bias is unlikely given the uniform vital status follow-up procedures used by our staff masked to participants’ CKD status levels. In our questionnaire, we had broad data on tobacco or alcohol use, diet, education, socioeconomic status, other possible confounders (e.g., insulin resistance), or the severity of disease. Few changes in diabetes treatment and health care over the short study period will have affected mortality results. Our study also specifically examined ESRD within the paradigm of a formal competing risks (Fine-Gray) model, which looked at the cumulative incidence of ESRD while taking into consideration (in an estimation sense) the competing risk of death. This strategy is especially important in patients with type 1 diabetes, since cause-specific analysis may be confounded when individuals at highest risk of ESRD (e.g., macroalbuminuric or hypertensive patients) are also at increased risk of pre-ESRD mortality.
Another strength of this study is the fact that the dietary intake of sodium in our cohort is very similar to that documented in the general population, both in Finland (13
) and globally (22
). We have also recently published dietary surveys on a subset of 817 FinnDiane patients, collected with a 3-day food record completed twice with a 2- to 3-month interval, describing a mean daily sodium consumption of 7.2 ± 2.0 g/day (23
). Twenty-seven percent of patients achieved target levels of less than 6 g of NaCl (23
), a figure no different to the general Finnish population. Such data suggest that advice to restrict dietary salt intake in our cohort of diabetic patients is not promulgated beyond universal recommendations for the general population or is equally ineffective. Although it is possible that more aggressive recommendations for salt restriction or their uptake may be more likely in high-risk patients (confounding by indication), the association between salt and adverse outcomes appeared to be independent of conventional factors that physicians may normally use to stratify risk.
It is fundamental to state with respect to the association of sodium and adverse outcomes that statistical independence of effect does not imply (strict) causality (24
) and additional trials should be performed to formally test our findings and the potential utility/risk of sodium restriction in the context of diabetes. Any pathophysiological mechanisms that may underlie our findings also remain to be established. Certainly, sodium restriction results in increased atherosclerosis in experimental models (25
). In humans, salt restriction increased activity of the renin-angiotensin-aldosterone system (4
) and increased sympathetic activity (3
) and insulin resistance (5
), each of which may contribute to the development and progression of diabetes complications. We were unable to observe any association between sodium intake and blood pressure indexes in our cohort. Consistent with these findings, short-term studies of salt restriction in patients with type 1 diabetes have also revealed variable outcomes, with both increases and falls in blood pressure observed in different individuals, and no net effect overall (17
). Notably, in this study, the clinical characteristics of salt-sensitive patients were not different from those in whom blood pressure levels rose with salt restriction, particularly with regard to the presence and severity of CKD. This suggests that even in the setting of diabetes and CKD, universal recommendations regarding salt intake may be problematic.
Several study limitations need to be considered. First, these studies were also limited by reliance on sodium excretion data obtained from a single urine collection. Because of dietary variability, there may be substantial variation in salt excretion on a day-to-day basis, meaning that a single value may not accurately reflect habitual sodium intake. Nonetheless, this method is regarded as the best way to estimate dietary sodium intake and substantially more effective than dietary recall. There appears to be only a modest coefficient of variation (21
), comparable with other commonly used parameters like lipid levels. Even in the setting of renal impairment, the urinary excretion of sodium is largely maintained along with volume homeostasis, as a result of adaptations in residual nephrons. This has been suggested to be because sodium intake may be physiologically set (22
). Second, our data are observational. Although observational studies have a number of potential advantages, it is also possible that associations demonstrated in this study may be because of confounding by unmeasured factors or ones that are difficult to quantify. For example, variability in dietary sodium intake may be passively associated with a range of differences in diet composition, processing, and preparation that may impact adverse outcomes in diabetic individuals. In addition, the appetite for salt may be associated with differences in neuroendocrine effectors that may themselves impact on the development and progression of diabetes complications.
In summary, the association between sodium intake and adverse outcomes in type 1 diabetes is complex. In the setting of type 1 diabetes, individuals with the lowest sodium excretion (the best available marker for their low salt intake) have an increased risk of all-cause mortality and ESRD. Individuals with a high salt intake also have an increased risk of mortality. Although we have not demonstrated causality, these findings further support the calls for caution before applying salt restriction universally (26
), since clinical outcomes may be different or paradoxical in certain settings. In particular, the specific requirements for diabetic individuals should not be inferred from general population data but must be validated in studies performed specifically in diabetic patients.