Association between glycemic control and chronic kidney disease development in older patients with type 2 diabetes: A retrospective cohort study

Mar Riera-Pagespetit; Gorka Gómez-Terrazas; Doris Xiomara Monroy-Parada; Cristian Tebé; Carlos Pérez-López; Silvia Miró Cañís; María José Castro-Castro; Anna Cortés-Bosch de Basea; Alejandro Rodríguez-Molinero

doi:10.1371/journal.pone.0353388

Peer Review History

Original SubmissionDecember 13, 2025
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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: The question is whether only one annual HbA1c measurement can speak about glycemic control in these patients? Immediately upon reading the instructions, the fear of possible biases (the influence of other factors on glycemia and kidney function, especially in this fragile population) arises. Searching the literature, I find that similar topics have already been covered. It is clear that generally poor glucoregulation implies a less functioning kidney. But in the elderly, it can be due to a number of other reasons besides the glycemic profile. Keywords: Somehow "diabetes control" and "glycemic control" sound the same, try to be more imaginative. Maybe instead of "renal function" in the title, write "development of renal dysfunction or failure or similar"? Just a suggestion. The binary division of glycemic control: black/white is also delicate. So, someone with an HbA1c of 7.4 has good control, while someone with 7.5 has bad control. It would be ideal to divide HbA1c differences of, for example, 0.5 into groups or classes in some other way to avoid such exclusivity, so we would get more credible results. Or as ACCORD maybe take below 7 and above 8 and let's see for those subgroups. Again, just as a suggestion. Is it by chance that the Abstract, Methods section, is written in a different font in the manuscript? Please avoid writing abbreviations at the beginning of sentences. Nicely written text but full of possible biases. We cannot draw such conclusions based on the analyzed data and without excluding potential other factors. It is certainly interesting that there were slightly more smokers and comorbidities in the group with better glucoregulation. Perhaps due to better awareness of the disease? And more ACEi and NSAID users, and better glucoregulation and eGFR. I like that we have that data. P16 L 286: "o" is probably missing an "r" (or). Finally, when I read everything, I congratulate you because this work has value. Reviewer #2: Overall a useful question to try to answer. I don't understand why you chose the cutoff HbA1c 7.5% to differentiate between poor 251 and good glycemic control. It seems like this was selected maybe based to get positive results? Most guidelines suggest <7% if risk of hypos and in T2DM. Other issues is the strongest confounder in octogenerians will be IHD / heart failure. There is no data on this. Another big concern is the absence or acknowledgement of any proteinuria data. This is known to have a strong impact on CKD progression. I understand may be unavailable due to historical data but you at least need to acknowledge this. I am also concerned that the good control ACEi / ARB use was 11.32% vs 6.83% in poor control. This is a difference of 4.5% in ACEi /ARB use. This must be confounding the matter and I wonder if the modest difference in good glycaemic control could be partially attributable to this. I am also concerned on the recommendations for tighter HbA1c control. The features of frailty and functionality are more important in octogenerians and I would not want individuals to interpret this as everyone needs tighter control risking hypos. ****** -->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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Revision 1
13 May 2026 Author Response We thank the Editor for the opportunity to revise the manuscript. We respond below point by point to the reviewers’ comments. Reviewer #1: Q: The question is whether only one annual HbA1c measurement can speak about glycemic control in these patients? ANSWER: We thank the reviewer for this important comment. We would like to clarify that the requirement of at least one HbA1c measurement per year was established as a minimum inclusion criterion to ensure adequate follow-up, rather than to define glycemic control based on a single measurement. In fact, glycemic control in our study was determined using multiple HbA1c values over the entire follow-up period, allowing for a longitudinal assessment rather than relying on a single time point. Consistent with routine clinical practice, patients in our cohort had more frequent measurements than the minimum required. Specifically, the mean number of HbA1c determinations was 1.53 per patient-year, resulting in multiple measurements per individual over the 5-year follow-up period. This approach strengthens the reliability of our classification of glycemic control and reduces the risk of misclassification due to isolated values. To improve clarity, we have revised the Methods section to better explain how HbA1c measurements were used to define glycemic control over time. Please see modifications in the first paragraph of the Objectives and Variables section. Q: Immediately upon reading the instructions, the fear of possible biases (the influence of other factors on glycemia and kidney function, especially in this fragile population) arises. Searching the literature, I find that similar topics have already been covered. It is clear that generally poor glucoregulation implies a less functioning kidney. But in the elderly, it can be due to a number of other reasons besides the glycemic profile. ANSWER: We fully agree that in older populations, particularly among frail individuals, both glycemic control and kidney function are influenced by multiple factors beyond glucose levels alone.To address this concern, we performed multivariable analyses adjusting for a broad set of clinically relevant covariates, including age, sex, year of inclusion, comorbidities (dyslipidemia, hypertension, obesity, smoking, and alcohol consumption), and pharmacological treatments (statins, ACE inhibitors, angiotensin receptor blockers, oral antidiabetics, NSAIDs, and insulin). We also agree that the association between poor glycemic control and renal impairment has been well established in the general adult population. However, evidence specifically focused on individuals aged ≥80 years remains scarce. In this context, our study contributes by examining this relationship in a very old population using a longitudinal design. Our findings do not suggest that glycemic control is the sole determinant of renal function in older adults, but rather that it remains a relevant factor within a complex clinical framework. This perspective has been further emphasized in the revised Conclusion section, where we explicitly acknowledge the multifactorial nature of CKD development in this population. Please see changes in the conclusion section. Q: Keywords: Somehow "diabetes control" and "glycemic control" sound the same, try to be more imaginative. ANSWER: We thank the reviewer for this suggestion. We have revised the list of keywords to avoid duplication and improve specificity. Q: Maybe instead of "renal function" in the title, write "development of renal dysfunction or failure or similar"? Just a suggestion. ANSWER: We thank the reviewer for this suggestion. We agree that the wording of the outcome in the title can be refined to better reflect the clinical nature of the study. In line with this comment, we have revised the title to improve clarity and better represent the focus on CKD development. Q: The binary division of glycemic control: black/white is also delicate. So, someone with an HbA1c of 7.4 has good control, while someone with 7.5 has bad control. It would be ideal to divide HbA1c differences of, for example, 0.5 into groups or classes in some other way to avoid such exclusivity, so we would get more credible results. Or as ACCORD maybe take below 7 and above 8 and let's see for those subgroups. Again, just as a suggestion. ANSEWER: We thank the reviewer for this thoughtful comment regarding the categorization of glycemic control. We agree that dichotomizing HbA1c values may oversimplify a continuous biological variable and could potentially lead to misclassification, particularly for individuals close to the selected threshold. This is a recognized limitation of categorical approaches and has been acknowledged in the revised Discussion section. However, our decision to use a binary classification with a threshold of 7.5% was based on clinical and methodological considerations. First, current international guidelines for older adults with type 2 diabetes (including ADA, IDF, and AGS) recommend individualized HbA1c targets within a relatively broad range (approximately 7.0–8.5%), rather than strict universal cut-offs. In this context, 7.5% represents a clinically meaningful and widely accepted intermediate target, particularly for older patients with intermediate health status. Additionally, this threshold is consistent with evidence from major trials such as ACCORD, where mean HbA1c levels around 7.5% were associated with safer outcomes compared to more intensive strategies. Second, the use of a binary classification facilitates clinical interpretability and allows for a clearer comparison between broadly defined “good” and “poor” glycemic control in a population where treatment goals are often simplified in routine practice. We acknowledge the reviewer’s suggestion of using multiple categories (e.g., 0.5% intervals or broader ranges such as <7%, 7–8%, >8%), which could provide a more granular understanding of the relationship between HbA1c and CKD risk. However, further stratification would have reduced the sample size within each subgroup and potentially limited statistical power, particularly in this specific population of patients aged ≥80 years. To address this concern, we have clarified the rationale for the chosen cut-off in the Methods and Discussion sections and explicitly acknowledged the potential limitations of dichotomization. We agree that future studies with larger samples should explore HbA1c as a continuous variable or using multiple clinically relevant categories to better characterize dose–response relationships. Please see modifications in the Objectives and Variables section, and the third paragraph of the discussion Q: Is it by chance that the Abstract, Methods section, is written in a different font in the manuscript? ANSWER: We thank the reviewer for this comment. Any formatting differences in the reviewed version were unintentional. We have carefully revised the manuscript to ensure a consistent format throughout in the resubmitted version. Q: Please avoid writing abbreviations at the beginning of sentences. ANSWER: Thank you, we have now avoided this throughout the text. Q: Nicely written text but full of possible biases. We cannot draw such conclusions based on the analyzed data and without excluding potential other factors. ANSWER: We thank the reviewer for this important comment. We agree that, given the observational nature of our study and the potential for residual confounding, the findings should be interpreted with caution and should not be considered as establishing a causal relationship. In response to this comment, we have revised the manuscript to ensure that the conclusions are more appropriately framed in terms of association rather than causation. We have also strengthened the Discussion section to further acknowledge potential sources of bias and unmeasured confounding factors that may influence the observed relationship. Please see changes in the Conclusion section of the manuscript and the Conclusion section of the abstract. Q: It is certainly interesting that there were slightly more smokers and comorbidities in the group with better glucoregulation. Perhaps due to better awareness of the disease? And more ACEi and NSAID users, and better glucoregulation and eGFR. I like that we have that data. ANSWER: We thank the reviewer for this insightful observation. We agree that some baseline characteristics, including a slightly higher prevalence of certain comorbidities, smoking, and the use of medications such as ACE inhibitors and NSAIDs in the group with better glycemic control, may appear counterintuitive. One possible explanation could be that patients with a higher burden of comorbidities have more frequent contact with healthcare services, which may facilitate closer monitoring and optimization of glycemic management. However, this interpretation remains speculative. Importantly, these variables were included in the multivariable analyses, and the association between glycemic control and CKD outcomes remained significant after adjustment. Therefore, while these differences are of interest, they are unlikely to fully explain the observed results. We have added a sentence in line with the reviewer’s comment in the discussion. Please see changes in the first paragraph of the discussion Q: P16 L 286: "o" is probably missing an "r" (or). ANSWER: Corrected, many thanks. Q: Finally, when I read everything, I congratulate you because this work has value. ANSWER: We thank the reviewer for this positive and encouraging comment. We are grateful for the reviewer’s insightful comments, which have contributed to improving the clinical interpretation and balance of our work. Reviewer #2: Overall a useful question to try to answer. Q: I don't understand why you chose the cutoff HbA1c 7.5% to differentiate between poor 251 and good glycemic control. It seems like this was selected maybe based to get positive results? Most guidelines suggest <7% if risk of hypos and in T2DM. ANSWER: While some guidelines suggest targets below 7% for younger or healthier individuals, most international recommendations (including those from the American Diabetes Association, American Geriatrics Society, and International Diabetes Federation) emphasize individualized glycemic targets in older patients, typically within a broader range of approximately 7.0% to 8.5%, depending on comorbidity burden, functional status, and risk of hypoglycemia. In this context, a target around 7.5% is frequently considered appropriate for older adults with intermediate health status and is also consistent with the mean HbA1c achieved in large clinical trials such as ACCORD [21] (N Engl J Med 2008;358:2545–59 ). Specifically, we chose the cutoff point according to the recommendations of the American Diabetes Association, which suggests <7.0-7.5 in otherwise healthy elderly people and <8.0 in those with diabetes and intermediate or complex health [18](Diabetes Care. 2024 Jan 1;47) In response to the reviewer's comment, we have cited in the Methods section the clinical guideline used to determine the cutoff point. Please see the first paragraph of the Objectives and Variables section. Q: Other issues is the strongest confounder in octogenerians will be IHD / heart failure. There is no data on this. ANSWER: We thank the reviewer for this important observation. We agree that ischemic heart disease and heart failure are highly prevalent conditions in octogenarians and may act as relevant confounders in the relationship between glycemic control and renal outcomes. These conditions are strongly associated with both kidney function decline and clinical decision-making regarding glycemic targets, and therefore could influence both the exposure and the outcome. Unfortunately, detailed data on ischemic heart disease and heart failure were not consistently available in the databases used for this study, which limited our ability to include these variables in the multivariable models. However, we attempted to partially account for cardiovascular burden by adjusting for related variables such as hypertension, dyslipidemia, and pharmacological treatments. We acknowledge that residual confounding due to unmeasured cardiovascular conditions cannot be excluded and may have influenced the observed associations. This limitation has now been explicitly addressed in the Discussion section. Importantly, despite this limitation, the association between glycemic control and CKD incidence remained significant after adjustment for multiple clinically relevant covariates, suggesting that glycemic control may still play an independent role. Nevertheless, future studies including more detailed cardiovascular data are warranted to further clarify this relationship. Please see the modifications in the limitations section, sixth paragraph of the discussion. Q: Another big concern is the absence or acknowledgement of any proteinuria data. This is known to have a strong impact on CKD progression. I understand may be unavailable due to historical data but you at least need to acknowledge this. ANSWER: We agree that proteinuria is a clinically relevant factor in the progression of chronic kidney disease and would have been informative to describe in our study population. Unfortunately, proteinuria data were not consistently available in the databases used. From an analytical perspective, the role of proteinuria in this context is complex. While it may be associated with both glycemic control and renal outcomes, it is also likely to lie along the causal pathway linking hyperglycemia and kidney function decline. Therefore, adjusting for proteinuria could potentially attenuate the association of interest. For this reason, and given the lack of consistent data, proteinuria was not included in the models. We have clarified this point and acknowledged the absence of proteinuria data in the Discussion section. In line with the reviewer's comment, we have added a paragraph to the discussion. Please see the 7th paragraph of the discussion. Q: I am also concerned that the good control ACEi / ARB use was 11.32% vs 6.83% in poor control. This is a difference of 4.5% in ACEi /ARB use. This must be confounding the matter and I wonder if the modest difference in good glycaemic control could be partially attributable to this. ANSWER: We thank the reviewer for this observation. First, we would like to clarify the figures reported for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in our study population. According to Table 2, the use of ACE inhibitors was 4.83% in the poor glycemic control group and 8.13% in the good control group, while ARB use was 2.30% and 3.19%, respectively. Therefore, although there is a slightly higher use of these medications in the good control group, the absolute differences are relatively small. Importantly, both ACE inhibitors and ARBs were included as covariates in the multivariable regression models (both logistic and Cox regression analyses). After adjustment for these treatments, the association between glycemic control and CKD incidence, as well as time to CKD onset, remained statistically significant. This suggests that the observed relationship is unlikely to be fully explained by differences in ACEi/ARB use. We agree that these medications may have a protective effect on renal outcomes and could act as confounders. For this reason, they were specifically included in the adjusted models. Nevertheless, as with any observational study, residual confounding cannot be entirely excluded and has been acknowledged in the Discussion section. Please see changes in the 6th paragraph of the discussion, dedicated to limitations, we have mentioned ACE inhibitors and ARBs among the potential confounding factors that we have sought to control. Q: I am also concerned on the recommendations for tighter HbA1c control. The features of frailty and functionality are more important in octogenerians and I would not want individuals to interpret this as everyone needs tighter control risking hypos. ANSWER: We fully agree with the reviewer and believe that a study with the characteristics of ours should not be interpreted in isolation as a basis https://doi.org/10.1371/journal.pone.0353388.r002
24 Jun 2026 Decision Letter - Natural Hoi Sing Chu, Editor, Natural Hoi Sing Chu, Editor Association Between Glycemic Control and Chronic Kidney Disease Development in Older Patients with Type 2 Diabetes: A Retrospective Cohort Study PONE-D-25-64900R1 Dear Dr. Rodríguez-Molinero, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Natural Hoi Sing Chu, Ph.D Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0353388.r003
Formally Accepted
Acceptance Letter - Natural Hoi Sing Chu, Editor, Natural Hoi Sing Chu, Editor PONE-D-25-64900R1 PLOS One Dear Dr. Rodríguez-Molinero, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Natural Hoi Sing Chu Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0353388.r004

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