Chronic kidney disease (CKD) is a common complication of type 2 diabetes and is associated with poor health outcomes. Despite advances in diabetes care, the prevalence of CKD in that patient population remains more than 25% and increases with the duration of diabetes. In the United States, type 2 diabetes is the leading cause of end-stage renal disease requiring dialysis or kidney transplantation, and CKD is associated with increased risks of cardiovascular events and mortality in patients with diabetes.
The development and progression of CKD (defined as persistently reduced glomerular filtration rate [GFR] or elevated urinary albumin excretion) may be prevented with interventions such as vitamin D and omega-3 fatty acid supplements. Previous clinical trials designed to evaluate the renal effects of vitamin D and omega-3 fatty acid supplements have been of short duration, only evaluated urine albumin excretion as an outcome, or examined kidney outcomes as secondary post hoc analyses.
Ian H. de Boer, MD, and colleagues conducted VITAL-DKD (Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease) to examine the efficacy and safety of vitamin D and omega-3 fatty acids for the prevention and treatment of CKD in patients with type 2 diabetes. Results were reported online in JAMA [doi:10.1001/jama.2019.17380].
VITAL-DKD was conducted among 1312 adults with type 2 diabetes who were recruited between November 2011 and March 2014 from all 50 US states as an ancillary study to the VITAL (Vitamin D and Omega-3 Trial) coordinated by a single center in Massachusetts. Follow-up was completed in December 2017.
Participants were randomized to receive Vitamin D3 (23000 IU/d) and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d) (n=370), vitamin D3 and placebo (n=333), placebo and omega-3 fatty acids (n=289), or two placebos (n=320) for 5 years. The primary outcome of interest was change in GFR estimated from serum creatine and cystatin C (eGFR) from baseline to year 5. Secondary outcomes included time to the composite outcome of at least a 40% decrease in eGFR from baseline, kidney failure, or death; time to at least a 40% decrease in eGFR from baseline; and change in urine albumin-creatinine ratio (ACR) from baseline to study year 5.
At baseline, mean age of study participants was 67.6 years and median duration of diagnosed diabetes was 6 to 10 years; 46% were women, and 31% were of racial or ethnic minority. The most commonly used glucose-lowering medications were biguanides, followed by sulfonylureas. Twenty percent of the cohort reported insulin use. Less than 10% reported using a dipeptidyl peptidase 4 inhibitor or glucagon-like peptide 1 receptor agonist; sodium-glucose cotransporter 2 inhibitors were not yet commercially available.
Eighty percent of the participants used antihypertensive medications, including 61% who used a renin-angiotensin system inhibitor. Mean eGFR at baseline was 85.8 mL/min/1.73 m2; 13% of participants (n=165) had eGFR <60 mL/min/1.73 m2. Nine percent of participants (n=117) had urine ACR of at least 30 mg/g, including 2% (n=24) with an ACR of at least 300 mg/g. A total of 1090 of the 1312 randomized participants (83%) provided at least one follow-up blood sample, including 934 at year 5. At least one follow-up urine sample was provided by 1091 participants, including 945 at year 5 after randomization.
At 2 years following randomization for vitamin D or placebo, adherence to at least two-thirds of study medications was reported by 92% of participants; at 5 years, the percentage was 88%; medication adherence was reported by 91% and 89%, respectively, at 2 and 5 years for omega-3 fatty acids (or matching placebo).
At year 2, mean serum 25(OH)D concentrations were 41.4 ng/mL for those in the Vitamin D group and 29.8 mg/mL for those in the vitamin D placebo group (P<.001). For participants in the omega-3 fatty acid group, mean omega-3 indexes at year 2 were 3.6% compared with 2.3% for those in the omega-3 fatty acid placebo group (P<.001).
Mean eGFR was 85.8 mL/min/1.73 m2 at baseline, 80.0 mL/min/1.73 m2 at year 2, and 73.5 mL/min/1.73 m2 at year 5. In the full analytic population, mean change in eGFR from baseline to year 5 was –12.7 mL/min/1.73 m2; among the 932 participants with eGFR data at both baseline and year 5, the mean change from baseline to year 5 was –12.4 mL/min/1.73 m2.
Mean change in eGFR from baseline to year 5 in the vitamin D3 group was –12.3 mL/min/1.73 m2 versus –13.1 mL/min/1.73 m2 with placebo. Mean change in eGFR was –12.2 mL/min/1.73 m2 in the omega-3 fatty acids group compared with –13.1 mL/min/1.73 m2 in the placebo group. At year 5, there was no significant difference in change in eGFR according to treatment and no significant interaction between treatment assignments.
Of the three prespecified secondary outcomes, there were no significant differences by treatment assignment for either intervention.
In comparisons of both vitamin D and omega-3 fatty acid supplementation with respective placebos, adverse events were similar. Kidney stones occurred in 58 patients (32 receiving vitamin D3 and 26 receiving placebo) and gastrointestinal bleeding occurred in 45 participants in the omega-3 fatty acid group and 17 in the placebo group.
Limitations cited by the authors included the modest numbers of eGFR and urine ACR measurements collected per participant, the insufficient numbers of events for surrogate kidney end points, and not receiving a serum sample from all participants to calculate year 5 eGFR.
In summary, the researchers said, “Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings to not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes.”
- The VITAL-DKD study was conducted to examine the efficacy and safety of vitamin D and omega-3 fatty acid supplementation to prevent and treat chronic kidney disease (CKD) in patients with type 2 diabetes.
- There were no significant differences in change in estimated glomerular filtration rate at 5 years between the groups receiving vitamin D or omega-3 fatty acid supplementation and those receiving the respective placebos.
- The use of vitamin D or omega-3 fatty acid supplementation to preserve kidney function in patients with type 2 diabetes is not supported by the findings of this study.