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Omega-3 and Vit D of No Benefit for Kidney Function in Diabetes

Miriam E. Tucker and Pam Harrison
November 08, 2019

Supplementation with vitamin D3 or omega-3 fatty acids had no effect on kidney function in adults with type 2 diabetes at 5 years, new research shows.

Lead author Ian H. de Boer, MD, presented the data at Kidney Week 2019: American Society of Nephrology Annual Meeting as part of a High-Impact Clinical Trials oral abstract session.

The results, from an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), were simultaneously published in JAMA.

"We hoped that vitamin D, omega-3 fatty acids, or both might help prevent kidney disease and its progression to more advanced stages among adults with type 2 diabetes, based on a large quantity of experimental studies, observational data, and preliminary clinical trials," de Boer, who is professor of medicine and associate director of the Kidney Research Institute of the University of Washington, Seattle, told Medscape Medical News.

"But our study showed quite clearly that this is not the case neither supplement helped maintain kidney function in the broad population of people with type 2 diabetes. The trial provides a strong message that we'll need to turn our attention elsewhere to prevent and treat kidney disease," he stressed.

In an editorial that accompanies the JAMA article, Anika Lucas, MD, and Myles Wolf, MD, write: "VITAL-DKD was a well-designed, well-executed, well-powered study with a definitive main message: in patients with type 2 diabetes, routine supplementation with vitamin D or omega-3 fatty acids has no role in primary prevention of incident chronic kidney disease (CKD) or slowing of eGFR loss."

And in a press briefing at Kidney Week, de Boer said: "Patients believe in both vitamin D and omega-3 fatty acids and it is all based on hope, but clinical trials for both drugs have been generally disappointing ... and this trial needs to be taken in the context of those other trials.

"How do you get through to patients? I don't know. People take supplements when they like, but I think that physicians and other healthcare providers need to make it clear that there is no evidence base for that," he stressed.

He added: "There is probably no harm to the low doses [that we used in the trial]. But I do have patients who are taking much higher doses [than we used in the trial], and that should be discouraged.

"There are clearly adverse effects from high doses of either of these supplements. The ... doses that we used in this study have been shown to be safe, they just aren't beneficial.'

'A Stark Lesson on the Chasm Between Association and Causation'

In their editorial, Lucas and Wolf point out that much of the excitement among the public and the medical community about the potential benefits of supplementation have arisen mostly from observational data linking vitamin D deficiency to a variety of illnesses, including hypertension, diabetes, cardiovascular disease, and cancer.

"Not long ago, vitamin D was riding high.... The lay press seized on this chorus of observational studies, testing of serum 25-hydroxyvitamin D levels proliferated, and supplementation with cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) increased substantially.... Then came the randomized clinical trials."

The contrast between the current VITAL-DKD results with the prior epidemiologic studies implicating vitamin D deficiency in various diseases "offers a stark lesson on the chasm between association and causation," they note.

"It now seems safe to conclude that many prior epidemiological associations between vitamin D deficiency and adverse health outcomes were driven by unmeasured residual confounding or reverse causality," say the editorialists, who are both of the Division of Nephrology at Duke University School of Medicine, Durham, North Carolina.

No Benefit for Primary or Secondary Outcomes

The parent VITAL trial found no significant cardiovascular or cancer prevention benefit of vitamin D or omega-3 fatty acids among 26,000 generally healthy patients, as reported by Medscape Medical News in 2018.

The VITAL-DKD ancillary study included 1312 adults with type 2 diabetes from around the United States. The participants were randomly assigned to receive either vitamin D3 (2000 IU/d; Pharmavite LLC) plus omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d; ProNova), vitamin D3 plus placebo, placebo plus omega-3 fatty acids, or two placebos, each for 5 years.

At baseline, the mean age of the participants was 67.6 years, and the median diagnosed diabetes duration was 6 to 10 years. Just fewer than half of the participants (46%) were women, and 31% were of racial or ethnic minority; 934 (71%) completed the study.

The primary endpoint, mean change in eGFR from baseline to year 5, was -12.3 mL/min/1.73 m2 with vitamin D3 vs -13.1 mL/min/1.73 m2 with placebo, for no significant difference.

Likewise, with omega-3 fatty acids, the mean eGFR change was -12.2 mL/min/1.73 m2 vs -13.1 mL/min/1.73 m2 with placebo.

At year 5, there was no significant difference in change in eGFR by treatment (0.9 mL/min/1.73 m2 for both vitamin D and omega-3 fatty acids vs placebo), and there was no significant interaction between treatment assignments (P = .42).

Similarly, none of three other prespecified outcomes differed significantly by treatment for either of the supplements.

The composite outcome of at least a 40% decline in eGFR, kidney failure, or death occurred in a total of 164 participants, with no difference by treatment (hazard ratios, 0.92 and 1.11 for vitamin D and omega-3 fatty acids, respectively, vs placebo).

The secondary outcomes of at least a 40% decline in eGFR and change in urine albumin-creatinine by year 5 also didn't differ significantly from placebo for either supplement.

Is There Still Hope for Supplementation?

Despite the definitively negative findings, Lucas and Wolf still see possibility for future studies, given that the study participants had nearly normal vitamin D levels at baseline.

This, they say, leaves open the question of whether the results would have differed had recruitment been restricted to patients with moderate or severe vitamin D deficiency, given that a post hoc subgroup analysis of patients with lower baseline vitamin D levels (<20 and 20–30 ng/mL) had suggested nonsignificant benefit of supplementation.

However, they point out, "Given the known benefits of vitamin D on skeletal health, it would be ethically challenging to randomize patients known to be vitamin D deficient to receive placebo for the duration needed to assess effects on CKD outcomes."

Another possibility, the editorialists suggest, might be a study of supplementation in patients with more advanced CKD or more severe albuminuria at baseline.

In response, de Boer told Medscape Medical News, "There was a signal that vitamin D might have benefit among subgroups of participants with low blood 25-hydroxyvitamin D concentrations or evidence of preexisting kidney disease at baseline.

"It's biologically plausible that these subgroups might benefit more from vitamin D, which is why we explored them, but the subgroup effects were not statistically significant and should be taken with a grain of salt.

"The optimal management of vitamin D abnormalities in patients who have chronic kidney disease, whether due to diabetes or not, remains to be determined. Clinical trials in kidney disease populations could still be helpful," he concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. de Boer reports receipt of consulting fees from Boehringer Ingelheim and Ironwood and equipment and supplies for research from Medtronic and Abbott. Wolf reports having served as a consultant for Akebia, AMAG, Amgen, Ardelyx, Diasorin, and Pharmacosmos.

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Reviewed on 11/11/2019
References
SOURCE: Medscape, November 08, 2019. JAMA. Published online November 8, 2019. Kidney Week 2019: American Society of Nephrology Annual Meeting: Abstract FR-OR138, presented November 8, 2019.

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