Beyond Cholesterol Lowering: Clinical Caution, Personalization, and Nutritional Integration in Statin Therapy
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn this review, the authors discuss the current clinical effectiveness of statin therapy, as well as the role of nutritional status in modulating statin efficacy. The topic is important. However, I think the manuscript in its current form raises substantial concerns regarding methodology, strength of claims and interpretative rigor.
- The methodology is insufficiently described. What is the search strategy? What criteria is followed for inclusion and exclusion? How many large cohort epidemiological studies do the author include in this review? How was the evidence selected and weighed? For example, is the statement, such as “20–30% of patients in secondary or high-risk prevention do not achieve clinically meaningful benefits”, based on the authors conclusion from reviewing various epidemiological studies, or just based on the conclusion from other review paper?
- Consistent with the missing methodology, the effect of statin therapy, as discussed in this manuscript, is descriptive, rather than quantitative with solid evidence. I suggest the authors list all the evidence as a table, such as 1). The authors / organization who launch the study; 2). How many patients are included; 3). The ethnicity; 4). Duration; 5). Risk level; 6). Effectiveness of stain therapy; 7) Side-effects observed.
- The authors should more explicitly distinguish between established clinical evidence (RCTs, meta-analyses) and preclinical or mechanistic hypotheses. For example, the discussion of adverse effects relies heavily on associative or controversial literature, without sufficient contextualization of causality or magnitude of risk.
- The authors state that statin discontinuation due to adverse effects does not increase cardiovascular mortality. While supported by selected studies, this conclusion is highly context-dependent (age, baseline risk, indication, duration of follow-up). Please clarify the populations to which this statement applies and explicitly acknowledge potential confounding such as healthy-user bias and reverse causation
- The authors discussed nutrition and statin therapy. However, only red yeast rice, Omega-3 fatty acids, and essential amino acids (EAA) supplementation have been raised as examples. Please justify the rationale for emphasizing these nutraceuticals, especially EAA, over others. I suggest the authors include a table comparing the nutraceuticals that have beneficial effects accompanying statin therapy.
- Figure 1 and Figure 4 are visually helpful to clarify the mechanism and diagnostic flow. Yet Figure 2 and Figure 3 are not quite necessary and somehow oversimplify the mechanism and mislead the possible causality.
Author Response
In this review, the authors discuss the current clinical effectiveness of statin therapy, as well as the role of nutritional status in modulating statin efficacy. The topic is important. However, I think the manuscript in its current form raises substantial concerns regarding methodology, strength of claims and interpretative rigor.
Answer. We thank this reviewer for their time and for the valuable and constructive suggestions provided. We believe that the revisions made in response to these comments have significantly improved the manuscript and have enhanced its suitability for publication.
The methodology is insufficiently described. What is the search strategy? What criteria is followed for inclusion and exclusion? How many large cohort epidemiological studies do the author include in this review?
Answer. We thank you for highlighting this important issue, which we acknowledge and agree with. Indeed, clarifying the search strategy is essential in the context of a systematic review. However, the present work is a narrative review. Accordingly, we conducted targeted searches in the main scientific databases to identify the most recent and relevant publications using keywords such as statins, cardiovascular risk, statin-associated muscle symptoms, malnutrition, and pleiotropic effects of statins, among others, depending on the specific chapter. Both preclinical and clinical studies were included; although it was specified which type of study we were referring to in each case, they were not separated into different chapters in order to make the treatment of a specific topic more homogeneous and, hopefully, comprehensible. While we recognize that the level of evidence provided by a narrative review is lower than that of a systematic review, we believe that narrative reviews have substantial practical and educational values. They allow the integration of heterogeneous evidence, pathophysiological mechanisms, and clinical perspectives into a coherent and accessible framework, thereby facilitating knowledge translation and supporting clinical decision-making. The aim of this paper is not to criticize, minimize, or overemphasize the role of statins, but rather to emphasize the importance of an integrated and personalized therapeutic approach, as a reminder of good clinical practice. This principle applies to all pharmacological therapies. Within this framework, we believe that nutrition plays a fundamental role in enhancing drug efficacy, mitigating adverse muscular effects, and ultimately improving treatment adherence and patients’ quality of life.
How was the evidence selected and weighed? For example, is the statement, such as “20–30% of patients in secondary or high-risk prevention do not achieve clinically meaningful benefits”, based on the authors conclusion from reviewing various epidemiological studies, or just based on the conclusion from other review paper?
Answer. As indicated in the text, the data were obtained from the literature, in the indicated case from a systematic review and meta-analysis by Navarese EP et al., JAMA 2018.
Consistent with the missing methodology, the effect of statin therapy, as discussed in this manuscript, is descriptive, rather than quantitative with solid evidence. I suggest the authors list all the evidence as a table, such as 1). The authors / organization who launch the study; 2). How many patients are included; 3). The ethnicity; 4). Duration; 5). Risk level; 6). Effectiveness of stain therapy; 7) Side-effects observed.
Answer. Thank you for your suggestion. Since the text is a narrative review, we have included a table listing the main nutraceuticals considered useful for reducing LDL-C in support of drug therapy. A systematic analysis of each of them is beyond the scope of this narrative review, however, we have expanded and added some information to the text.
The authors should more explicitly distinguish between established clinical evidence (RCTs, meta-analyses) and preclinical or mechanistic hypotheses. For example, the discussion of adverse effects relies heavily on associative or controversial literature, without sufficient contextualization of causality or magnitude of risk.
Answer. The difference between study types (preclinical, RCTs, meta-analyses) has been explicitly stated in the text. We preferred not to separate them into paragraphs in order to provide a more accurate overview of the issue under consideration and avoid redundant repetition of the same concepts.
The authors state that statin discontinuation due to adverse effects does not increase cardiovascular mortality. While supported by selected studies, this conclusion is highly context-dependent (age, baseline risk, indication, duration of follow-up). Please clarify the populations to which this statement applies and explicitly acknowledge potential confounding such as healthy-user bias and reverse causation
Answer. We have modified the sentence in the introduction, hoping to have made it clearer.
The authors discussed nutrition and statin therapy. However, only red yeast rice, Omega-3 fatty acids, and essential amino acids (EAA) supplementation have been raised as examples. Please justify the rationale for emphasizing these nutraceuticals, especially EAA, over others. I suggest the authors include a table comparing the nutraceuticals that have beneficial effects accompanying statin therapy.
Answer. We've further highlighted the rationale for the usefulness of EAAs for muscle benefit in combating SAMS. Additionally, we've included a table listing the main nutraceuticals believed to be useful for reducing LDL-C and their clinical benefits when added to statins.
Figure 1 and Figure 4 are visually helpful to clarify the mechanism and diagnostic flow. Yet Figure 2 and Figure 3 are not quite necessary and somehow oversimplify the mechanism and mislead the possible causality.
Answer. We appreciate the insight and agree that Figures 2 and 3 are simplistic compared to the actual mechanisms involved. However, their purpose is to visually simplify the sequences that we believe to be fundamental to understanding the origin of SAMS (Figure 2), as well as the importance of EAAs in promoting and maintaining mitochondrial function and muscle mass, which are compromised by statin therapy and so potentially mitigate SAMS (Figure 3).
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors argue that statins provide minimal clinical benefit in primary prevention and low- to moderate-risk patients. Many large meta-analyses have shown that the proportionality of risk reduction from statin therapy is determined by the decline in LDL-C in mmol/L.
Dietary factors have been identified as a key feature in the impact of statin effectiveness; however, I believe that the patients genetic background may be even more important. How is dietary intake classified as a possible causal association (a potential confounder or modifier for the complete mechanism of action) of the effect of statins on the individual? How do the author(s) propose that we distinguish between these three possibilities?
The authors have developed a more cautious way of developing clinical practice guidelines using the data collected regarding the use of statins. What is the way the authors have developed to offer more personalized options of therapy while still being consistent with a public health framework that is based on an evidence-based approach to health?
Many parts of the review are cited to demonstrate the withdrawal of statin therapy and, therefore, as evidence that there has not been an increased risk of cardiovascular mortality associated with stopping statin therapy; do the authors possess data to support these conclusions?
Additionally, the review references studies that correlate the use of statins with an increased risk of insulin resistance, type 2 diabetes, and several types of cancers associated with statin use. Many studies have described neutral or protective effects.
In discussing pleiotropic effects, the manuscript notes the ongoing debate regarding their clinical relevance. Could the authors differentiate mechanistic plausibility from the demonstrated clinical impact more clearly?
This manuscript discusses the use of nutraceuticals (red yeast rice, omega-3 fatty acids, CoQ10, and plant sterols) as adjunctive strategies. Given the heterogeneity and limited quality of evidence, how important are these nutraceuticals? Please provide the exact effect on lowering mortality or events in comparison with statins.
Red yeast rice is pharmacologically active and is regulated as a drug in Europe. Does its inclusion as a “nutritional” option risk blurring the distinction between dietary supplementation and pharmacotherapy
Several nutraceuticals have been discussed despite neutral or negative randomized trial results. Is this hypothesis-generating?
The EAA supplementation section is well detailed, both mechanistically and in terms of thickness. The clinical evidence base for EAA supplementation in the management of muscle problems due to statins is rather limited - Is there enough evidence from clinical data to support the use of this approach? Most of the studies and trials reviewed in this section are either considered "preclinical" or only "small clinical" studies.
Author Response
We thank this reviewer for their time and for the valuable and constructive suggestions provided. We believe that the revisions made in response to these comments have significantly improved the manuscript and have enhanced its suitability for publication. We would like to underline that the manuscript is a narrative review. Accordingly, we conducted targeted searches in the main scientific databases to identify the most recent and relevant publications using keywords such as statins, cardiovascular risk, statin-associated muscle symptoms, malnutrition, and pleiotropic effects of statins, among others, depending on the specific chapter. Both preclinical and clinical studies were included. While we recognize that the level of evidence provided by a narrative review is lower than that of a systematic review, we believe that narrative reviews have substantial practical and educational values. They allow the integration of heterogeneous evidence, pathophysiological mechanisms, and clinical perspectives into a coherent and accessible framework, thereby facilitating knowledge translation and supporting clinical decision-making. The aim of this paper is not to criticize, minimize, or overemphasize the role of statins, but rather to emphasize the importance of an integrated and personalized therapeutic approach, as a reminder of good clinical practice. This principle applies to all pharmacological therapies. Within this framework, we believe that nutrition plays a fundamental role in enhancing drug efficacy, mitigating adverse muscular effects, and ultimately improving treatment adherence and patients’ quality of life.
The authors argue that statins provide minimal clinical benefit in primary prevention and low- to moderate-risk patients. Many large meta-analyses have shown that the proportionality of risk reduction from statin therapy is determined by the decline in LDL-C in mmol/L.
Answer. We have modified the sentence in the introduction, hoping to have made it clearer.
Dietary factors have been identified as a key feature in the impact of statin effectiveness; however, I believe that the patients genetic background may be even more important. How is dietary intake classified as a possible causal association (a potential confounder or modifier for the complete mechanism of action) of the effect of statins on the individual? How do the author(s) propose that we distinguish between these three possibilities?
Answer. In our opinion dietary intake may act both as a potential confounder and as an effect modifier in the relationship between statin therapy and cardiovascular outcomes, given its independent association with statin use and adherence, baseline cardiovascular risk, and treatment response. It is for these reasons that with this narrative review I wanted to highlight the importance of a personalized approach to therapy that considers both genetic factors and other clinical and physiological variables, as well as nutrition.
The authors have developed a more cautious way of developing clinical practice guidelines using the data collected regarding the use of statins. What is the way the authors have developed to offer more personalized options of therapy while still being consistent with a public health framework that is based on an evidence-based approach to health?
Answer. We did not question the evidence of effectiveness emerging from the vast literature. We have simply highlighted some well-known limitations of the RCTs on which the guidelines are based. In our opinion, and as explained in the text, the guidelines remain an important tool, but their application must be carefully evaluated by the doctor and adapted to the peculiar characteristics of each patient.
Many parts of the review are cited to demonstrate the withdrawal of statin therapy and, therefore, as evidence that there has not been an increased risk of cardiovascular mortality associated with stopping statin therapy; do the authors possess data to support these conclusions?
Answer. Thanks for the report. Being a narrative review we have no original data. In the introduction we changed the sentence about CV risk which was not written correctly.
Additionally, the review references studies that correlate the use of statins with an increased risk of insulin resistance, type 2 diabetes, and several types of cancers associated with statin use. Many studies have described neutral or protective effects.
Answer. We have explored the link between statins, diabetes, and cancer.
In discussing pleiotropic effects, the manuscript notes the ongoing debate regarding their clinical relevance. Could the authors differentiate mechanistic plausibility from the demonstrated clinical impact more clearly?
This manuscript discusses the use of nutraceuticals (red yeast rice, omega-3 fatty acids, CoQ10, and plant sterols) as adjunctive strategies. Given the heterogeneity and limited quality of evidence, how important are these nutraceuticals? Please provide the exact effect on lowering mortality or events in comparison with statins.
Answer. We add a list the main nutraceuticals considered useful in containing LDL-C levels. We agree with the general poor utility and conflicting results of many nutraceuticals. A systematic analysis of each of them is beyond the scope of this narrative review, however, we have expanded and added some information to the text.
Red yeast rice is pharmacologically active and is regulated as a drug in Europe. Does its inclusion as a “nutritional” option risk blurring the distinction between dietary supplementation and pharmacotherapy.
Answer. We agree with the observation. However, red yeast rice, when prescribed as nutritional supplement, the monacolin K content should not exceed 3 mg/day. For this reason, it is included in the nutraceutical.
Several nutraceuticals have been discussed despite neutral or negative randomized trial results. Is this hypothesis-generating?
Answer. The main nutraceuticals have been briefly described to provide the reader with an overview, although not exhaustive, of them, whose function seems to contribute to reducing LDL-C. The aim we pursue in the manuscript, however, does not concern the reduction of LDL-C which statins obviously provide, but to highlight the nutrients useful for reducing the damage resulting from the therapy, in particular at the muscle level, as proteins and above all EAA.
The EAA supplementation section is well detailed, both mechanistically and in terms of thickness. The clinical evidence base for EAA supplementation in the management of muscle problems due to statins is rather limited - Is there enough evidence from clinical data to support the use of this approach? Most of the studies and trials reviewed in this section are either considered "preclinical" or only "small clinical" studies.
Answer. To date, there is no direct clinical evidence supporting the use of essential amino acid (EAA) supplementation specifically for the prevention of statin-associated muscle symptoms (SAMS). Accordingly, the discussion is primarily based on evidence from preclinical studies and small clinical trials. Nevertheless, as outlined in the text and summarized in Figure 3, the effects of a complete blend of EAAs in stoichiometric proportions on the stimulation of muscle anabolism under hypercatabolic conditions are well characterized at the molecular level. Therefore, given the recognized role of nutrition in supporting patients undergoing pharmacological therapy, supplementation with a complete blend of EAAs may represent a rational adjunct to diet and medical treatment, with the potential to mitigate the risk or severity of drug-related adverse muscle effects.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThis review article has been improved after revision. However, although the authors argue that it is a narrative review, I still think more information about the studies they cited should be given, not only state only the conclusion. For example, Line 72, "Clinical data indicate that 20–25% of patients discontinue statins within 1–2 years, and that 5–10% experience true intolerance [12]." When the authors state this, they should also describe that in this study (Stroes, E.S. et al.; European Atherosclerosis Society Consensus Panel.), how many patients were included, and what the background the patients were in (race, age, etc.). Stating the conclusion directly in this manner may be misleading to readers. There are many similar statements without detailed background information in the manuscript.
Author Response
We thank the referee for taking the time to review the revised version of the manuscript. As suggested, where possible, we have added more methodological details regarding bibliographic citations.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe responses from the authors read like polite acknowledgments rather than evidence-based, point-by-point rebuttals.
Author Response
We thank the referee for taking the time to review the revised version of the manuscript. We respect the opinion expressed by the referee, but we want to explain. We note that our responses were intended to be substantive rather than merely polite. Each reviewer's comment was addressed with specific responses and/or revisions to the manuscript where appropriate. We remain fully available to further clarify any specific issues that may still appear to be unresolved. For this purpose, we would be very grateful if the reviewer could indicate which specific points they feel were insufficiently addressed, so that we can further improve the manuscript.
Round 3
Reviewer 2 Report
Comments and Suggestions for AuthorsAs mentioned in the previous rounds, my suggestion is to reject the paper as there are no hard data that support the statements presented in the paper.
