In our 15-year longitudinal observational follow-up study, we found very low levels of plasma vitamin D (less than the 10th percentile) to be a strong and independent predictor of all-cause mortality in type 2 diabetic patients. Low levels of vitamin D were also predictive of cardiovascular mortality. These associations were not only independent of glycemic control and conventional cardiovascular risk factors including known ischemic heart disease but also were independent of kidney function.
Severe vitamin D deficiency at baseline did not predict progression to microalbuminuria or macroalbuminuria. Our findings of associations between severe vitamin D deficiency and increased risk of all-cause and cardiovascular mortality in type 2 diabetic patients complement recent data from studies suggesting similar associations in the general population (4
) and among patients with nondiabetic CKD (6
) or ESRD (15
A cross-sectional study on 13,331 participants from NHANES III found low vitamin D levels to be associated with all-cause mortality (4
). Furthermore, a follow-up study on 1,739 Framingham Offspring Study participants showed that the incidence of nonfatal cardiovascular events was increased among participants with low vitamin D levels (3
). A study on mainly nondiabetic patients with CKD found vitamin D to independently predict all-cause mortality, cardiovascular events, and increased risk of progression to dialysis (6
Vitamin D is stored in its inactive form in the liver and in peripheral fat tissue for the body to extract and activate by hydroxylation in the liver and kidney, respectively. In healthy subjects, vitamin D deficiency can result from inadequate intake of vitamin D–containing foods coupled with inadequate sunlight exposure. Seasonal variations in vitamin D levels occur, depending on geographic latitude and sun exposure in particular. A study done on the general population in a Northern European country showed a seasonal variation of vitamin D insufficiency of 73 and 29% for winter and summer, respectively. The difference for vitamin D deficiency was similarly found to be 8 and 1% (16
). Furthermore, there are several conditions, such as obesity, absorption, and liver or kidney disorders, in which the risk of developing vitamin D deficiency is increased for physiological reasons.
Obesity is common among patients with type 2 diabetes. Vitamin D stored in fat tissue causes decreased bioavailability, and exposes obese patients at greater risk of developing vitamin D insufficiency. However, in the present study, the patients in the two subgroups did not differ significantly in BMI. There is no linear association between BMI and vitamin D in these data. Diabetic patients are more prone to developing CVD compared with the general population (17
). Having a higher risk profile, a greater treatment potential exists if vitamin D is also found to be a risk factor for CVD development and mortality.
The role of vitamin D deficiency in prevalent cardiovascular disease is in a cross-sectional study of type 2 diabetic patients with mild kidney impairment, shown to be strongly associated with a higher prevalence of manifest cardiovascular disease, also after adjustment for baseline kidney function and other known CVD risk factors (18
With the present longitudinal follow-up study we are now able to show that the predictive value of low vitamin D levels on all-cause and cardiovascular mortality, already shown for the general population and in patients with nondiabetic CKD, also applies to type 2 diabetic patients.
The mechanisms of action behind the survival benefit seen among patients with the higher levels of vitamin D at baseline are unclear. A growing amount of evidence indicates that vitamin D through activation of the vitamin D receptor has clinically important pleiotropic effects involved in CVD development and mortality. Vitamin D has been associated with suppression of the renin-angiotensin-aldosterone system (RAAS) (19
), cardiac myocyte hypertrophy (20
), vascular calcification, atherosclerosis-lowering, anti-inflammatory (21
), and immunomodulatory actions (1
), suggesting cardiovascular and renoprotective effects. Furthermore, vitamin D deficiency has been associated with increased incident risk of certain cancers as well as a higher mortality from these cancers (1
Several of the above-mentioned pathways may be important mechanisms in cardiovascular health. Inflammation is a key mechanism in atherosclerosis. A recent study in type 2 diabetic patients, investigating the mechanism by which vitamin D deficiency mediates increased risk of cardiovascular disease, found reduced vitamin D receptor signaling to be a potential mechanism underlying increased foam cell (macrophages who ingested oxidized LDL) formation and accelerated cardiovascular disease in diabetic compared with nondiabetic patients (22
Given the observational design, the present study does not elaborate further on underlying mechanisms but adds to the increasing amount of data suggesting that vitamin D substitution might be a potential therapeutic target to prevent vascular disease progression. In this study there was a significant difference in known diabetes duration between groups with low and higher levels of vitamin D, but duration of diabetes and level of vitamin D were not associated and we adjusted for known duration of diabetes in our Cox models. In a type 1 diabetes cohort, we have recently presented a similar predictive effect of low vitamin D levels (C.J., personal communication, American Society of Nephrology, 2009). Analysis of subgroups based on duration of diabetes of more or less than 11 years, suggested that the effect was stronger in patients with long duration; however, because of the reduced power, such analysis should be interpreted with caution.
The pathogenesis behind diabetic kidney disease is complex and thought to involve multiple pathways. Of particular importance is an activation of the intrarenal RAAS promoting progressive renal injury. In mice, 1,25-dihydroxyvitamin D3
is shown to be a negative endocrine regulator of the RAAS on transcriptional level independent of calcium and PTH (19
). Agarwal et al. (9
) analyzed data from three randomized controlled clinical trials investigating administration of oral paricalcitol in patients with CKD. They showed that paricalcitol caused a reduction in albuminuria as measured by a dipstick method compared with placebo (P
= 0.004). Importantly, the effects seemed to be independent of concomitant therapies to inhibit the RAAS. Furthermore, it has recently been shown that administration of a VDRA in addition to blockade of the RAAS causes sustained albuminuria reduction and thereby has clinically relevant renoprotective effects in patients with CKD (23
) (D. de Zeeuw, personal communication, American Society of Nephrology, 2009).
Because of circumstantial evidence on the beneficial effects seen when one is intervening with VDRA, it is tempting to speculate that low levels of vitamin D might be a risk marker of both initiation and/or progression of albuminuria in diabetic patients (9
). Our study, however, did not find vitamin D levels <13.9 nmol/l to significantly predict either initiation or progression of albuminuria.
In our study, severe vitamin D deficiency was defined as the lower 10th percentile [25(OH)D3
<13.9 nmol/l] in both men and women. An international consensus in regard to definitions of which vitamin D levels are to be thought of as normal, insufficiency, and deficiency is lacking. The limits for a physiological optimal vitamin D level are still a matter of debate in the literature. Although vitamin D is shown to be stable in stored samples (13
), storing could affect absolute concentrations due to evaporation; thus, we chose the 10th percentile. As mentioned, the stability of plasma vitamin D levels in our samples was tested before analysis was done on the present cohort and found not to show any statistically significant difference in levels when samples from different years of storage were compared.
Our study has some strengths and limitations. One element of methodological strength is the longitudinal design and long follow-up period and completeness of follow-up. Given the observational design, it is not possible to infer causality from the associations described.
Secondary hyperparathyroidism in patients with CKD is known to predict increased all-cause and cardiovascular mortality (24
). The question arises whether the observed predictive effect of vitamin D is merely to be considered as a marker for other associated risk factors. We did not measure parathyroid hormone at baseline, and therefore we were not able to exclude this vitamin D-dependent variable as a driving confounder in our analysis. However, kidney function was adjusted for, and still the association between vitamin D and increased mortality persisted.
Further limitations of our study are related to possible changes in the level of vitamin D throughout the year. We did not adjust for seasonal change nor did we have baseline data on physical activity that could be related to outdoor activity and sun exposure and thereby level of vitamin D. We were therefore not able to adjust for this.
More observational studies are needed to confirm our findings. Randomized controlled clinical trials administering VDRA are necessary to prove causality between vitamin D status and survival prognosis in diabetic patients.
In summary, baseline levels of 25(OH)D3 less than the 10th percentile predict increased risk of all-cause and cardiovascular mortality in type 2 diabetic patients. Baseline levels of 25(OH)D3 less than the 10th percentile do not predict progression to micro- or macroalbuminuria.