Avalilação PREreview de Dietary Carboxymethyllysine: Short-Term Intake Reduction in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease

Write a short summary of the research’s main findings and how this work has moved the field forward.

This article assesses whether the temporary intake of the primary end-products of glycation, carboxymethyllysine (CML), can reduce circulating CML in elderly individuals with type 2 diabetes mellitus and coronary artery disease. The authors state that the low-CML diet led to a substantial decrease in the estimated dietary AGE/CML exposure and a meaningful decrease in serum CML in a 15-day randomised dietary intervention. Increased intake of fibre and reduced intake of trans fat, polyunsaturated fat, and cholesterol were also linked with the intervention, and correlations indicated possible relationships between serum CML, oxidative stress, body water, and dietary AGEs.

The article advances the research by studying a high-risk, clinically important population with T2DM and CAD, and dietary AGE restriction may be of particular relevance. It is also practical as it tests an intervention based on food preparation, indicating that it could be possible to reduce exposure with methods of cooking and dietary advice in real-world practice. Despite its preliminary character, the evidence is favourable to the hypothesis according to which the dietary AGE lowering may be an adjustable nutritional approach that should be experimented with in longer and larger clinical studies.

Major issues

• List significant concerns about the research, if there are any.

1. The participants used in the study are only 36 and are only followed for over 15 days. That is sufficient to identify short-term changes in diet, but not adequate to justify wider conclusions concerning vascular protection, metabolic enhancement or thwarting diabetes complications. The conclusions are to be restructured as tentative and to generate hypotheses.

2. The primary focus of the manuscript is on within-group pre/post comparisons. In a randomised trial, the most important question is whether the intervention group was more changed than the control group. The article would have been far more robust if it had included between-group comparisons of change of baseline, hopefully including effect sizes and confidence intervals. In the absence of that, it is more difficult to determine whether the perceived differences are real because of intervention or time, variation in measurements or change of behaviour among both groups.

3. Numerous dietary, anthropometric, biochemical, and correlation results are analysed in the manuscript. This increases the chances of false positives in a small trial. There is a possibility that some statistically significant results are due to multiple testing as opposed to strong biological action. The authors need to be able to find a main outcome and be more reserved on secondary and exploratory findings.

4. The intervention did not separate CML reduction. It also altered fibre, cholesterol and other elements of the diet. This complicates the process of pinpointing the serum CML decrease, or any metabolic explanation, to CML restriction and not to a more favourable overall dietary pattern. This should be brought out more in the discussion.

5. The paper is based on a food database created in the context of a different environment and modified to regional foods. Since AGE content depends on ingredients, processing, and cooking conditions, this can introduce exposure misclassification. This is particularly due to the fact that dieting for AGE reduction is the main focus of the study hypothesis. The authors state this, but its implication on internal validity need to be addressed more directly.

6. Even though serum CML had gone down, the majority of metabolic and anthropometric outcomes had not changed significantly in 15 days. There are others that have trends that are reported in a manner that may exaggerate their meaning. The distinction of change of biomarkers and clinically meaningful patient benefit could be better defined in the paper.

7. The analysis of serum CML is found to correlate with various or a few biochemical or body composition measures, with some surprising negative correlations with lipids and glucose. These analyses are extremely susceptible to chance results and confounding in a small sample, particularly in a medicated population. Such findings must be in the form of exploratory and not mechanistic evidence.

8. The manuscript ought to describe in a more explicit manner how randomisation has been carried out, in addition to whether allocation was concealed, whether laboratory assessors were blinded, how compliance to the dietary intervention measure was assessed, and whether analysis was intention-to-treat or per-protocol. This information is required in order to determine the risk of bias.

Minor issues

• List concerns that would improve the overall flow or clarity but are not critical to the understanding and conclusions of the research.

1. The grammar is also faulty, and the phrasing is clumsy, with repetitions of words used, and there are punctuation mistakes present in the manuscript. Close editing in the English language would enhance readability to a great extent.

2. The idea of phrases implying vascular and metabolic protection or complications avoidance needs to be diluted unless there is more clinical evidence to back it up. The terms of use ought to be consistent with a short-term study of biomarkers.

3. Findings of p-values of about 0.07 to 0.09 are talked about over and over again as suggestive gains. This may erase the difference between observed and unobserved effects. They ought to be characterised with more precautions.

4. It would be beneficial to define the main outcome in a more straightforward manner, specify precise units in a constant manner and take into account a column of change versus baseline. Certain labels on tables and abbreviations should also be standardised.

5. This is assisted by the addition of a flow diagram, although reporting could be enhanced with additional information on the trials, such as randomisation, how the trial was handled, and endpoint definitions should have been better described.

6. As an illustration, the discussion of bone mass does not seem to go hand in hand with the table values and might require a correction or explanation. The authors ought to take pains to ensure that each interpretation is appropriate to the direction of effect that is reported.

7. The paper switches between CML, dAGEs, dietary AGEs, and similar terminologies in a manner that can be quite confusing to the readers. Easy and unambiguous terms would enhance the flow.

8. This would assist the readers in knowing the extent to which the results can be generalised to the general population of patients with T2DM and CAD.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they did not use generative AI to come up with new ideas for their review.