Insulin Resistance/Hyperinsulinemia Should Be Considered in the Prevention and Treatment of Essential Hypertension

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is perspective article aimed to present the facts about this area of interest, essential or primary hypertension as disease of unknown cause. But the authors presented opinion suggesting insulin resistance can be analysed not only as risk factor, but the main cause of essential hypertension. There are some minor issues to be resolved:

 

1. Please define clearly the aim of this perspective
2. Reference list should be more up to date
3. Line 136-139, please put the reference
4. Line 165-175, , please put the reference
5. There are some basic references from this area of investigation, which are not insluded in this article, please put them into perspective of this manuscript : N Engl J Med 1987;317:350-357;

Ferrannini E, Haffner SM, Stern MP. Essential hypertension: an insulin-resistant state. J Cardiovasc Pharmacol. 1990;15 Suppl 5:S18-25. PMID: 1694927.; Hypertension. 2013;62:404-409

Author Response

Comments and Suggestions for Authors Rev.1

This is perspective article aimed to present the facts about this area of interest, essential or primary hypertension as disease of unknown cause. But the authors presented opinion suggesting insulin resistance can be analysed not only as risk factor, but the main cause of essential hypertension. There are some minor issues to be resolved:

 

1. Please define clearly the aim of this perspective

Aut. Thank you. We have now defined the aim of this article.

 

1. Reference list should be more up to date

Aut. Thank you. We added many other references

 

1. Line 136-139, please put the reference

Aut. Ok. Made.

 

1. Line 165-175, , please put the reference

Aut. Ok. Made

 

1. There are some basic references from this area of investigation, which are not insluded in this article, please put them into perspective of this manuscript : N Engl J Med 1987;317:350-357;

Ferrannini E, Haffner SM, Stern MP. Essential hypertension: an insulin-resistant state. J Cardiovasc Pharmacol. 1990;15 Suppl 5:S18-25. PMID: 1694927.; Hypertension. 2013;62:404-409

          Aut. Thank you, we have added these important references.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The article proposes that essential hypertension is a unidirectional consequence of insulin resistance. In many cases, this may be true (for example, high fructose or high-fat diet models). However, it fails to consider that both disorders may also share a common cause. For example, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, capillary rarefaction, immune activation, or even obesity can cause both insulin resistance and hypertension. The authors also overlook the fact that drugs that increase insulin sensitivity do not necessarily lower blood pressure. Finally, insulin resistance and diabetes also occur in endocrine hypertensive disorders, such as hypercortisolism, acromegaly, and pheochromocytoma.

The order in which the references are cited in the text does not correspond to their numbering in the References section.

Author Response

Comments and Suggestions for Authors Rev. 2

The article proposes that essential hypertension is a unidirectional consequence of insulin resistance. In many cases, this may be true (for example, high fructose or high-fat diet models). However, it fails to consider that both disorders may also share a common cause. For example, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, capillary rarefaction, immune activation, or even obesity can cause both insulin resistance and hypertension. The authors also overlook the fact that drugs that increase insulin sensitivity do not necessarily lower blood pressure. Finally, insulin resistance and diabetes also occur in endocrine hypertensive disorders, such as hypercortisolism, acromegaly, and pheochromocytoma.

Aut. We thank the reviewer for his precious suggestion and have changed the text accordingly.

The order in which the references are cited in the text does not correspond to their numbering in the References section.

Aut. Thank you for your observation. We have corrected the reference numbering.

 

Reviewer 3 Report

Comments and Suggestions for Authors

 

1. The manuscript repeatedly presents the claim that insulin resistance is the main or even sole cause of essential hypertension with unwarranted certainty (e.g., “insulin resistance… must be identified as the main, if not sole, cause of essential hypertension”), yet provides no balanced discussion of competing mechanisms or heterogeneity in hypertensive phenotypes.

 

 

2. Several narrative statements equate association with causation. For example, citing meta-analyses reporting HR values around 1.4–1.7 and then concluding that insulin resistance “explains” most hypertension is not supported by the magnitude or nature of the reported associations, which remain observational and confounded.

 

 

3. The manuscript lacks any formal statistical or epidemiologic framework for causal inference. There is no mention of confounding, mediation, temporality, or causal models (e.g., DAGs). Strong causal assertions therefore appear methodologically unsupported.

 

 

4. Evidence from Mendelian randomization is used as definitive causal proof, yet the manuscript does not discuss instrument strength, horizontal pleiotropy, or sensitivity analyses. Presenting MR findings as conclusive overstates the certainty of these results.

 

 

5. The article does not address reverse causality, despite hypertension itself worsening insulin sensitivity through vascular stiffness and neurohormonal activation. Ignoring bidirectionality weakens the interpretation of observational associations.

 

 

6. Mechanistic pathways (ET-1/NO imbalance, sympathetic activation, renal sodium retention, RAAS stimulation) are listed without quantifying their relative contribution to blood pressure variance. Statements such as “all these mechanisms can easily explain the onset of hypertension” oversimplify complex physiology.

 

 

7. Epidemiological claims are made in the absence of quantitative evidence. For instance, the assertion “most forms of essential hypertension are associated with insulin resistance” is not supported with prevalence ratios, conditional probabilities, or data stratified by BMI, age, sex, or ethnicity.

 

 

8. The manuscript does not compare the effect size of insulin resistance with other major predictors of hypertension (e.g., age, sodium intake, kidney disease, genetics). Without multivariable or adjusted estimates, the argument that insulin resistance is the dominant driver remains unsubstantiated.

 

 

9. Many cited risk estimates come from minimally adjusted models, yet the manuscript does not discuss how these associations attenuate after adjusting for adiposity, diet, physical activity, renal function, or socioeconomic factors. This omission risks overstating the independent role of insulin resistance.

 

 

10. The argument that insulin resistance prevalence (30–40%) matches essential hypertension prevalence and therefore must be its primary cause is a logical fallacy. Similar prevalence does not imply etiologic equivalence, yet the manuscript treats these numbers as confirmatory.

 

 

11. The narrative asserts that hyperinsulinemia is “ignored” clinically, comparing it to conditions like Cushing’s disease or hyperthyroidism. This comparison is statistically misleading because guidelines recommend treating the underlying metabolic disease rather than insulin levels themselves; the manuscript oversimplifies endocrine management.

 

 

12. Claims regarding the superiority of treating insulin resistance to control hypertension are made without presenting effect sizes from interventional trials. None of the lifestyle or pharmacologic interventions listed (metformin, SGLT2 inhibitors, GLP-1 agonists, berberine, quercetin, etc.) are supported with quantitative data demonstrating blood pressure reduction independent of weight loss.

 

 

13. The recommendation to reclassify essential hypertension as “insulin-resistant hypertension” is not supported by epidemiological modeling such as population-attributable fractions, risk stratification analyses, or comparative predictive performance against standard risk factors.

 

 

14. The article relies heavily on the authors’ own prior publications (refs 24–26), raising concerns of circular citation. Broader high-quality external studies, guideline summaries, and randomized trial data should be incorporated for balance.

 

 

15. Important hypertensive subgroups (e.g., lean normometabolic hypertensives, elderly patients with arterial stiffness, salt-sensitive individuals) are not addressed, leading to an overgeneralized etiologic claim that does not reflect clinical reality.

 

 

16. The figure summarizing insulin resistance as a cause of hypertension, diabetes, cardiovascular disease, cancer, and neurodegeneration presents all links as equivalent, without distinguishing between well-established vs. hypothesized relationships. This risks overstating the strength of evidence.

 

 

17. Policy-level statements (e.g., “scientific community and health institutions need to be convinced”) appear advocacy-driven rather than evidence-driven, and are not supported by statistical modeling of public-health impact or cost-effectiveness.

 

 

18. The manuscript lacks a limitations section. There is no acknowledgement of residual confounding, measurement error in IR indices (HOMA-IR, TyG), population heterogeneity, or the modest effect sizes typical of metabolic predictors of hypertension.

 

 

19. Statements implying that controlling insulin resistance would substantially reduce antihypertensive drug use are not backed by quantitative evidence, clinical trials, or modeling; these claims therefore appear speculative rather than data-driven.

 

Author Response

Comments and Suggestions for Authors

Dear Reviewer, we thank you for the accurate revision of our manuscript and for your precious suggestions. With our work we are trying to stimulate the scientific community and Health Institution of the various countries to address the issue of IR/Hyperin more definitively, to determine with Absolute certainty whether it should be considered a cause of several major pathologies such as arterial hypertension, type 2 diabetes mellitus, and others. If so, IR/Hyperin would finally be treated as the other major risk factors. However, we agree with you and have accepted most of your suggestions. First of all, we have changed the concept of IR/Hyperin as main cause of essential hypertension in contributing or one of the causes, and have also changed the title of the manuscript.

1. Reviewer. The manuscript repeatedly presents the claim that insulin resistance is the main or even sole cause of essential hypertension with unwarranted certainty (e.g., “insulin resistance… must be identified as the main, if not sole, cause of essential hypertension”), yet provides no balanced discussion of competing mechanisms or heterogeneity in hypertensive phenotypes. 
2. Authors. we have changed the concept of IR/Hyperin as main cause of essential hypertension in contributing or one of the causes, and have also changed the title of the manuscript.

 

2. Reviewer. Several narrative statements equate association with causation. For example, citing meta-analyses reporting HR values around 1.4–1.7 and then concluding that insulin resistance “explains” most hypertension is not supported by the magnitude or nature of the reported associations, which remain observational and confounded. 
3. Authors. We agree with you and have changed the sentence.
4. Reviewer. The manuscript lacks any formal statistical or epidemiologic framework for causal inference. There is no mention of confounding, mediation, temporality, or causal models (e.g., DAGs). Strong causal assertions therefore appear methodologically unsupported.
5. Authors. We agree that there are no formal statistical or epidemiological framework for causal inference, therefore we have changed the concept.

 

4. Reviewer. Evidence from Mendelian randomization is used as definitive causal proof, yet the manuscript does not discuss instrument strength, horizontal pleiotropy, or sensitivity analyses. Presenting MR findings as conclusive overstates the certainty of these results.
5. Authors. We agree with your observation and have made changes accordingly.
6. Reviewer. The article does not address reverse causality, despite hypertension itself worsening insulin sensitivity through vascular stiffness and neurohormonal activation. Ignoring bidirectionality weakens the interpretation of observational associations. 
7. Authors. We agree with the Reviewer and nave added a sentence and a reference in the text.
8. Reviewer. Mechanistic pathways (ET-1/NO imbalance, sympathetic activation, renal sodium retention, RAAS stimulation) are listed without quantifying their relative contribution to blood pressure variance. Statements such as “all these mechanisms can easily explain the onset of hypertension” oversimplify complex physiology. 
9. Authors. Unfortunately, we are not able to quantify their relative contribution with certainty. However, we have written a sentence to explain the concept.
10. Reviewer. Epidemiological claims are made in the absence of quantitative evidence. For instance, the assertion “most forms of essential hypertension are associated with insulin resistance” is not supported with prevalence ratios, conditional probabilities, or data stratified by BMI, age, sex, or ethnicity. 
11. Authors. We agree with the Reviewer, However, we have included a sentence and references which report the prevalence of insulin resistance, assessed by euglycemic-hyperinsulinemic clamp, in hypertensive patients.
12. Reviewer. The manuscript does not compare the effect size of insulin resistance with other major predictors of hypertension (e.g., age, sodium intake, kidney disease, genetics). Without multivariable or adjusted estimates, the argument that insulin resistance is the dominant driver remains unsubstantiated.
13. Authors. We are unable to compare the effect size of IR with that of other major predictors of hypertension. However, we strongly discourage in the text the notion that IR/Hyperin should be considered the sole or primary cause of hypertension.
14. Reviewer. Many cited risk estimates come from minimally adjusted models, yet the manuscript does not discuss how these associations attenuate after adjusting for adiposity, diet, physical activity, renal function, or socioeconomic factors. This omission risks overstating the independent role of insulin resistance. 
15. Authors. Thank you. We agree with the Reviewer and, as already told, the concept of IR as sole cause of essential hypertension has been attenuated.
16. Reviewer. The argument that insulin resistance prevalence (30–40%) matches essential hypertension prevalence and therefore must be its primary cause is a logical fallacy. Similar prevalence does not imply etiologic equivalence, yet the manuscript treats these numbers as confirmatory. 
17. Authors. We agree with the concept that similar prevalence does not imply etiologic equivalence and, in fact, we didn’t say this in the text. However, as already said has been shown an high prevalence of IR in lean hypertensive subjects without diabetes.
18. Reviewer. The narrative asserts that hyperinsulinemia is “ignored” clinically, comparing it to conditions like Cushing’s disease or hyperthyroidism. This comparison is statistically misleading because guidelines recommend treating the underlying metabolic disease rather than insulin levels themselves; the manuscript oversimplifies endocrine management.
19. Authors. We agree with the Reviewer and nave changed the sentence accordingly.
20. Reviewer. Claims regarding the superiority of treating insulin resistance to control hypertension are made without presenting effect sizes from interventional trials. None of the lifestyle or pharmacologic interventions listed (metformin, SGLT2 inhibitors, GLP-1 agonists, berberine, quercetin, etc.) are supported with quantitative data demonstrating blood pressure reduction independent of weight loss 
21. Authors. We have added a paragraph and references to support the concept that pharmacologic intervention to improve insulin sensitivity can nave positive effects on blood pressure values.
22. Reviewer. The recommendation to reclassify essential hypertension as “insulin-resistant hypertension” is not supported by epidemiological modeling such as population-attributable fractions, risk stratification analyses, or comparative predictive performance against standard risk factors. 
23. Authors. We agree with the reviewer and nave changed the concept.
24. Reviewer. The article relies heavily on the authors’ own prior publications (refs 24–26), raising concerns of circular citation. Broader high-quality external studies, guideline summaries, and randomized trial data should be incorporated for balance. 
25. Authors. Thank you, we have added other references as alsi suggested by other review.
26. Reviewer. Important hypertensive subgroups (e.g., lean normometabolic hypertensives, elderly patients with arterial stiffness, salt-sensitive individuals) are not addressed, leading to an overgeneralized etiologic claim that does not reflect clinical reality. 
27. Authors. Thank you. We have not considered other hypertensive subgroups. However, IR has been shown in lean (normometabolic in whom was not measured IR) hypertensives, salt sensitive hypertensives are often also insulin resistant subjects because salt sensitivity can induce IR (Ertuglu LA, Elijovich F, Laffer CL, Kirabo A. Salt-Sensitivity of Blood Pressure and Insulin Resistance. Front Physiol. 2021 Dec 13;12:793924. doi: 10.3389/fphys.2021.793924. PMID: 34966295; PMCID: PMC8711096.). Aging and IR are strictly associated (Kurauti MA, Soares GM, Marmentini C, Bronczek GA, Branco RCS, Boschero AC. Insulin and aging. Vitam Horm. 2021;115:185-219. doi: 10.1016/bs.vh.2020.12.010. Epub 2021 Feb 1. PMID: 33706949).

16.Reviewer.  The figure summarizing insulin resistance as a cause of hypertension, diabetes, cardiovascular disease, cancer, and neurodegeneration presents all links as equivalent, without distinguishing between well-established vs. hypothesized relationships. This risks overstating the strength of evidence. 

16. Authors. We agree and have changed the caption of the figure accordingly.
17. Reviewer. Policy-level statements (e.g., “scientific community and health institutions need to be convinced”) appear advocacy-driven rather than evidence-driven, and are not supported by statistical modeling of public-health impact or cost-effectiveness. 
18. Authors. Accordingly with your suggestion we have changed the sentence.
19. Reviewer. The manuscript lacks a limitations section. There is no acknowledgement of residual confounding, measurement error in IR indices (HOMA-IR, TyG), population heterogeneity, or the modest effect sizes typical of metabolic predictors of hypertension.
20. Authors. We have added a short paragraph with limitations

 

19. Reviewer. Statements implying that controlling insulin resistance would substantially reduce antihypertensive drug use are not backed by quantitative evidence, clinical trials, or modeling; these claims therefore appear speculative rather than data-driven.
20. Authors. We have changed this sentence with the support of a reference showing that the association metformin plus fosinopril produced a best control of blood pressure compared to treatments with single substances.

 

 

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript entitled Essential hypertension should be renamed insulin-resistant hypertension is an article type perspective. The authors stated that probably, most of the cases of essential hypertension are caused by insulin resistance. Therefore, they analyzed if the insulin resistance could be the main, if not the sole, cause of the all forms of essential hypertension, therefore classifying these forms as “insulin-resistant arterial hypertensions”.

This manuscript seems interesting, but all arguments invoked by the authors does not sustain the causality between insulin-resistance and essential hypertension.

Major revision

The fact that the insulin resistance is associated with hypertension does not means a causality between these. Neither the fact that essential arterial hypertension and insulin resistance have a comparable prevalence. Even the strong relationship between insulin resistance and the risk of developing hypertension it is not the argument in favor for a such statement (and title).

Taking into consideration all above arguments I think that the authors should change de title.

Minor revision

In Conclusions the authors repeat the same ideas at least two times.

 The abstract is repeated in Introduction.

Author Response

Comments and Suggestions for Authors R.4

We thank very much the reviewer for his  important suggestions.

The manuscript entitled Essential hypertension should be renamed insulin-resistant hypertension is an article type perspective. The authors stated that probably, most of the cases of essential hypertension are caused by insulin resistance. Therefore, they analyzed if the insulin resistance could be the main, if not the sole, cause of the all forms of essential hypertension, therefore classifying these forms as “insulin-resistant arterial hypertensions”.

This manuscript seems interesting, but all arguments invoked by the authors does not sustain the causality between insulin-resistance and essential hypertension.

Major revision

Rev. The fact that the insulin resistance is associated with hypertension does not means a causality between these. Neither the fact that essential arterial hypertension and insulin resistance have a comparable prevalence. Even the strong relationship between insulin resistance and the risk of developing hypertension it is not the argument in favor for a such statement (and title).

Aut. We agree with the Reviewer that a clear causality can not be demonstrated and have changed this concept and the title.

Taking into consideration all above arguments I think that the authors should change de title.

Minor revision

Rev. In Conclusions the authors repeat the same ideas at least two times.

Aut. Yes, thank you. We have changed.

Rev. The abstract is repeated in Introduction.

Aut. Thank you. We have modified the abstract and introduction.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The article has been improved substantially.

Author Response

We thank the Reviewer for id words of appreciation of the revised version.

Reviewer 3 Report

Comments and Suggestions for Authors

The new version shows some surface-level improvements in language and organization, but the fundamental scientific and conceptual problems present in the old version remain essentially unresolved. The manuscript continues to present the central claim—that essential hypertension is primarily or even solely caused by insulin resistance—as a causal conclusion rather than a hypothesis, despite relying almost entirely on observational associations. For example, the new version states that “most forms of essential hypertension are associated with insulin resistance, which is their unrecognized main cause,” which is only a rephrasing of the old version’s deterministic assertions and still lacks mechanistic or interventional evidence. Likewise, the new text preserves overly definitive proposals such as “Essential hypertension should be classified as hypertension due to insulin resistance” and “It is time to identify patients with insulin resistance early in the general population,” despite providing no rigorous basis for such public-health recommendations. The therapeutic section, although shortened, still implies guideline-discordant clinical practice—for instance suggesting that insulin-sensitizing agents should accompany antihypertensive therapy—without adequate evidence or acknowledgment of risks. Overall, while the new version appears stylistically improved, it fails to address the core scientific concerns, continues to overstate causality, and presents speculative ideas as established facts. For these reasons, the revision is insufficient, and rejection is recommended.

Author Response

We  agree with the Reviewer 3 on the fact that there is an association between IR/Hyperin and EH bug not a sufficiently demonstrated causal link. This is because this causal link gas not been sufficiently studied, even if there is a strong association which should not be overlooked. However, according to the Reviewer's suggestions we have changed the title and all the sentencesthat talk about a causal link between IR/Hyperin and EH with sentences that underline the association between the two, concluding that researches are needed to demonstrate with Absolute certainty whether IR/Hyperin can be considered one of the causes of EH.

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you for responding to my comments.

Author Response

We thank the Reviewer for his words of appreciation of the revised version.

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

The authors strictly underlined the possibility in stead of direct casual relatiinship. Thank you. The article can be published as is.