24th November 2019, Dr Chee L Khoo
It’s not often that we report on trials with negative results but this trial attracted my attention because of many issues it raised when the top-line results were announced in the Journal of American Medical Association a fortnight ago. The conclusion states “supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years.”. Are those conclusions valid?
In theory, Vitamin D and omega-3 fatty acids (O3FA) supplementation should improve renal function in patients with diabetes and chronic kidney disease (CKD) or at least slow down the progression of renal disease in these patients. In animal models, 1,25-OH Vit D3 and its analogues suppress the renin-angiotensin system, reduce kidney inflammation and fibrosis, exert pro-survival effects on podocytes and reduce albuminuria and glomerulo-sclerosis (1,2) while O3FA have anti-inflammatory, anti-thrombotic, and vascular properties that may help prevent CKD (3). In humans, lower circulating concentrations of 25-OH-Vitamin D, lower dietary intake of fish and lower plasma polyunsaturated O3FA concentrations have been associated with increased risk of albuminuria and GFR decline in many studies (3-6).
The Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease (VITAL-DKD) was designed to assess the efficacy and safety of vitamin D and O3FA for prevention and treatment of CKD in patients with type 2 diabetes. The VITAL-DKD was a subset of the parent trial, VITAL which is a randomised, double-blind, placebo-controlled trial of vitamin D and marine O3FA for primary prevention of cardiovascular disease and cancer. Participants were randomised to 1) Vit D + O3FA, 2) Vit D + placebo, 3) O3FA + placebo or 4) placebo only.
If you only looked at the summary of study, you would easily conclude that Vit D + O3FA does not prevent deterioration of renal function in patients with diabetes kidney disease, right? Well, we better look at the details of the study.
The 1320 participants had a mean age of 67.6 years old with a mean duration of diabetes of 6-10 years. The participants were followed up for 5 years (2011-2016). Metformin and sulphonylureas were the most commonly used anti-diabetic medications. 20% of the participants were on insulin but only 10% were on either a DPP4 inhibitor or GLP1-RA. The SGLT2 inhibitors were not available at the time of the trial. Only 61% of the participants were on ACE inhibitors.
The primary outcome was change in eGFR while the secondary outcomes were: 1) time to the composite outcome of at least a 40% decrease in eGFR from baseline, kidney failure, or death; 2) time to at least a 40% decrease in eGFR from baseline and 3) change in urine albumin-creatinine ratio (ACR) from baseline.
Mean baseline eGFR was 85.8 mL/min/1.73m2. Only 13% of the participants had an eGFR of <60 ml/min/1.73 m2. Only 9% had urine ACR of > 3.35 mg/mmol and only 2% had urine ACR of > 33 mg/mmol. Only about 15% of participants have vitamin D levels < 20 ng/ml. Most participants had near normal vitamin D levels. The mean eGFR declined from 85.8 to 73.5 mL/min/1.73m2 (12.7% drop) over the 5 years. There were no difference between the treatment groups. None of the secondary outcomes were different between the treatment groups.
To me, the findings were not terribly exciting. Most participants had pretty good renal function with reasonably good eGFR. Very few participants had significant microalbuminuria. Most participants had near normal Vitamin levels.
This illustrates that we need to read conclusions or abstracts from studies carefully. In a time poor environment, it’s easy to skim through headlines and not delve into the actual study to critically appraise the findings. We are still unsure whether Vitamin D and/or O3FA has a role in slowing the progression of renal impairment in patients with diabetes. This study really doesn’t add to our knowledge base.
We now have the SGLT2 inhibitors which have preliminary data suggesting renal benefits.
- Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC. Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc Natl Acad Sci U S A. 2008;105(41): 15896-15901. doi:10.1073/pnas.0803751105
- Ito I,Waku T, Aoki M, et al. A nonclassical vitamin D receptor pathway suppresses renal fibrosis. J Clin Invest. 2013;123(11):4579-4594. doi:10.1172/JCI67804
- Shapiro H, Theilla M, Attal-Singer J, Singer P. Effects of polyunsaturated fatty acid consumption in diabetic nephropathy. Nat Rev Nephrol. 2011;7(2): 110-121. doi:10.1038/nrneph.2010.156
- de Boer IH, Katz R, Chonchol M, et al. Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. Clin J AmSoc Nephrol. 2011;6(9):2141-2149. doi:10.2215/CJN.02640311
- de Boer IH, Sachs MC, Cleary PA, et al; Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Circulating vitamin D metabolites and kidney disease in type 1 diabetes. J Clin Endocrinol Metab. 2012;97(12):4780-4788. doi:10.1210/jc.2012-2852
- Miller ER III, Juraschek SP, Appel LJ, et al. The effect of n-3 long-chain polyunsaturated fatty acid supplementation on urine protein excretion and kidney function: meta-analysis of clinical trials. Am J Clin Nutr. 2009;89
- IH de Boer, LR Zelnick, J Ruzinski, G Friedenberg, J Duszlak, VY Bubes, AN Hoofnagle, R Thadhani, RJ Glynn, JE Buring, HD Sesso, JE Manson. Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2019;322(19):1899-1909. doi:10.1001/jama.2019.17380