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The role of vitamin D in diabetic complications – prognostic impact and therapeutic potential

Christel Jørgensen

Summary

English Summary The classical and well-known role of active vitamin D, calcitriol (1,25(OH)2D) is regulation of the calcium and phosphate homeostasis. An accumulating amount of data suggests extraskeletal effects for vitamin D. Vitamin D deficiency is highly prevalent worldwide. Severe vitamin D deficiency has been associated with increased risk of all-cause mortality. Furthermore, low vitamin D levels have been associated with increased risk of cardiovascular morbidity and mortality. Therapy with a vitamin D receptor activator is reported to reduce albuminuria. Patients with diabetes mellitus have an increased risk of cardiovascular morbidity and mortality and the risk increases with the presence of diabetic kidney disease. Diabetic kidney disease is the leading cause of ESRD in the western world and new treatments are warranted. The role of vitamin D in development and progression of diabetic kidney disease, in cardiovascular morbidity and in all-cause mortality is not fully understood. 

Based on study I, II and III of this thesis I evaluate the role of vitamin D as a risk marker for development and progression of microvascular complications (retinopathy and albuminuria), cardiovascular morbidity and mortality as well as all-cause mortality in patients with diabetes mellitus. Furthermore with study IV I investigated the effects of active vitamin D analogue (paricalcitol) therapy on primarily cardiovascular and renal endpoints in type 1 diabetes for new insights into potential causality. 

This thesis is based on the following four studies: 1. Joergensen C, Gall MA, Schmedes A, Tarnow L, Parving H-H, Rossing P: Vitamin D levels and mortality in type 2 diabetes. Diabetes Care 2010; 33(10):2238-2243. 2. Joergensen C, Hovind P, Schmedes A, Parving HH, Rossing P. Vitamin D levels, microvascular complications, and mortality in type 1 diabetes. Diabetes Care 2011; 34(5):1081-1085. 3. Joergensen C, Reinhard H, Schmedes A, Hansen PR, Wiinberg N, Petersen CL et al. Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate. Diabetes Care 2012; 35(1):168-172. 4. Joergensen C, Tarnow L, Goetze JP, Rossing P: Vitamin D analogue therapy, cardiovascular risk and kidney function in type 1 diabetic patients with diabetic nephropathy – a randomized trial (DRAFT).  

In study I, we examined in a follow-up study whether low vitamin D levels predicted an increased risk of all-cause and cardiovascular mortality as well as progression of albuminuria in 289 patients with type 2 diabetes mellitus. Median follow-up was 15 years. We found that patients with low vitamin D levels at baseline had nearly twice the risk of both all-cause and cardiovascular mortality compared to patients with higher vitamin D levels. These associations persisted after adjustment for known cardiovascular risk factors, HbA1c and renal function. We found no statistically significant association between low vitamin D levels and increased risk of progression in albuminuria. 

In study II we investigated in a follow-up study whether low vitamin D levels predicted an increased risk of all-cause mortality and progression in microvascular complications (retinopathy and albuminuria) in an inception cohort of 220 patients with type 1 diabetes mellitus. Median follow-up was 26 years. We found that patients with low vitamin D levels at baseline had more than twice the risk of death from all causes after adjustment for known cardiovascular risk factors, UAER and HbA1c. We found no statistically significant association between low vitamin D levels and increased risk of progression in either retinopathy or albuminuria. 

In study III we investigated in a cross-sectional study the association between low levels of vitamin D and the presence of asymptomatic significant CAD among 200 type 2 diabetic patients with elevated UAER and no history of CVD. Among all 200 patients the prevalence of severe deficiency of vitamin D was 9.5%. Among the 70 patients diagnosed with significant CAD during the study, the prevalence of severe vitamin D deficiency was 53%. We found a significant association between severe vitamin D deficiency and asymptomatic significant CAD. In study IV, a randomised placebo controlled cross-over study in 45 type 1 diabetic patients with diabetic nephropathy, we studied the effects of active vitamin D analogue therapy compared to placebo on the primary endpoint, a change in plasma proBNP concentration (surrogate marker for cardiovascular morbidity and mortality in patients with diabetes) and on kidney function (UAER, eGFR and measured GFR). Paricalcitol therapy did not significantly affect p-proBNP. We did find however that urinary albumin excretion was significantly decreased during paricalcitol compared to placebo therapy. In conclusion my results support existing research suggesting associations between vitamin D and cardiovascular morbidity and mortality as well as all-cause mortality in patients with diabetes. Additionally, I am able to show that active VDA therapy reduces urinary albumin excretion significantly compared to placebo therapy in patients with type 1 diabetes and diabetic nephropathy.