Effect of Vitamin D Supplementation on Cardiometabolic Outcomes in Older Australian Adults—Results from the Randomized Controlled D-Health Trial

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study titled “Effect of vitamin D supplementation on cardiometabolic outcomes in older Australian adults – results from the randomized controlled D-Health Trial” aims to determine whether monthly supplementation with 60,000 international units (IU) of vitamin D3 affected the prevalence of hypertension, hypercholesterolaemia, or Type 2 Diabetes Mellitus (T2D), using new prescriptions of relevant medications as a proxy for diagnosis.

There was no direct measurement of baseline serum 25(OH)D; instead, predicted values from a model (AUC 0.71, indicating only moderate accuracy) were used. This limits subgroup validity, particularly for analyses of "low vitamin D" status.

"Incident hypertension/hypercholesterolaemia/T2D" is defined by new prescriptions, which  misses cases that have not been diagnosed or treated.

There is a risk of misclassifying individuals who take medications for reasons other than their intended use.

Selection bias is present: participants were healthier, predominantly of European descent, and more educated than the national average, resulting in limited external validity. Exclusion of non-consenting participants for data linkage (8.5%) may introduce systematic differences, even though randomisation does not affect consent rates.

Were the assumptions of proportional hazards rigorously evaluated in every model?

Why were non-linear dose-response relationships not investigated?

There may be insufficient power for the T2D subgroup due to the low number of events (4.4% incidence).

There is no adjustment for the false discovery rate in multiple subgroup analyses.

The authors state that "vitamin D supplementation had no material effect"; however, this may apply only to a vitamin D–sufficient, older Australian cohort.

It should be emphasised that null findings do not rule out benefits in deficient populations.

There is very little mechanistic interpretation; the discussion could elaborate further on how lifelong exposure (as shown in Mendelian studies) differs from late-life intervention.

Why was baseline 25(OH)D not measured directly, at least in a representative subsample, to validate the predictions?

How do the results compare with similar studies in populations with insufficient vitamin D?

Was attrition or use of supplements outside the study considered?

Did subgroup analyses by BMI or predicted vitamin D show any trends approaching significance?

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors conducted an intervention trial using vitamin D supplements in a large cohort of older adults and performed a 5-year follow-up study using a drug prescription database, with outcomes including the development of hypertension, dyslipidemia, and type 2 diabetes. The results did not demonstrate disease- prevention effects of vitamin D, but the study is nonetheless interesting. The reviewer has some questions.

Taking a certain medication may affect the effect of vitamin D supplements. Individuals receiving treatment for a disease would habitually visit medical institutions and are likely to have opportunities to begin treatment for other diseases. When the analysis was limited to individuals not receiving any medication, what were the results?

To initiate treatment for hypertension, dyslipidemia, or type 2 diabetes, people need to know the clinical tests, such as those obtained during health checkups. Was there a difference in health check-up attendance between the intervention group and the control group?

Minot points

Line 52: “T2D” should be spelled out.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The experimental results are predominantly negative. While negative findings can still hold positive significance, the outcomes of this study appear particularly weak. I believe many of the experimental data hold analytical value, but the authors did not analyze these data. Such results seem to have limited value for publication.

Abstract: The Methods section is overly detailed and should be shortened.

Introduction: This section should incorporate data to discuss the hazards of the three chronic diseases, particularly data related to mortality and morbidity rates.

Introduction: The background and rationale for conducting this study need to be strengthened.

Please expand on the value and significance of this study at the end of the Introduction.

Please check the manuscript details, as some places are missing punctuation marks.

The Methods section is too fragmented; I believe many subsections could be merged.

The Discussion should compare findings with those of other scholars, such as the correlation between vitamin D supplementation and chronic diseases, and discuss the reasons for any discrepancies. However, the current discussion lacks depth.

There is a need for an in-depth discussion of the manuscript's limitations, as only one limitation is currently mentioned.

The authors did not discuss why their findings are inconsistent with those of observational studies.

Please incorporate recent references, as some of the current references are outdated.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors responded positively to my concerns.

Reviewer 2 Report

Comments and Suggestions for Authors

Authors replied to the comments of the reviewer appropriately.

Reviewer 3 Report

Comments and Suggestions for Authors

Approved