Unfortunately, cardiovascular diseases and cancers are still the leading causes of death in developed and developing countries despite the considerable progress made in the prevention and treatment of diseases. Maybe we missed something? Insulin resistance (IR) with associated hyperinsulinemia (Hypein) is a silent pandemic whose prevalence is continually growing in developed and developing countries, now exceeding 51% of the general population. IR/Hypein, despite the vast scientific literature supporting its adverse action on the development of type 2 diabetes, cardiovascular alterations, tumors, neurological disorders, and cellular senescence, is not yet considered an independent risk factor and, therefore, is not screened in the general population and adequately treated. There are now numerous substances, drugs, and natural substances that, in association with the correction of a wrong lifestyle, can help to reduce IR/Hypein. We are convinced that the time has come to implement a prevention plan against this critical risk factor. Therefore, this manuscript aims to highlight IR/Hypein as an independent risk factor for type 2 diabetes, cardiovascular diseases, cancers, cellular senescence, and neuropsychiatric disorders, supporting our conviction with the available scientific literature on the topic.

Heart failure (HF) has become a subject of continuous interest since it was declared a new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated. It is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. During the last two decades, it was possible to see that the prevalence of heart failure with preserved ejection fraction (HFpEF) was increasing while that of heart failure with reduced ejection fraction (HFrEF) was decreasing. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance (IR)/hyperinsulinemia (Hyperins) in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, over 50% of patients with HF also have IR/Hyperins, and the percentage is even higher in those with HFpEF. In the scientific literature, it has been well highlighted that the increased circulating levels of insulin, associated with conditions of insulin resistance, are responsible for progressive cardiovascular alterations over the years that could stimulate the development and/or the worsening of HFpEF. The aim of this manuscript was to review the scientific literature that supports a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community toward the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in the development and worsening of HF, believing that its adequate screening in the general population and an appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

Despite all the progress made by science in the prevention and treatment of cardiovascular diseases and cancers, these are still the main reasons for hospitalizations and death in the Western world. Among the possible causes of this situation, disorders related to hyperinsulinemia and insulin resistance (Hyperin/IR) are still little-known topics. An analysis of the literature shows that this condition is a multiple risk factor for type 2 diabetes, cardiovascular diseases, cellular senescence and cancer, and neurodegenerative diseases. Hyperin/IR is progressively increasing worldwide, and its prevalence has now exceeded 50% of the general population and in overweight children. Asymptomatic or poorly symptomatic, it can last for many years before manifesting itself as diabetes, cardiovascular disease, neoplasm, cognitive deficit, or dementia, therefore leading to enormous social and healthcare costs. For these reasons, a screening plan for this pathology should be implemented for the purpose of identifying people with Hyperin/IR and promptly starting them on preventive treatment.

This review aims to show, by an analysis of the literature on the topic, that hyperinsulinemia associated with insulin resistance is a multiple risk factor for type 2 diabetes, cardiovascular diseases, cellular senescence and cancer, and neurodegenerative diseases. This condition is progressively increasing in developed and developing countries, and its prevalence has now exceeded 50% of the general population. Since it is asymptomatic or poorly symptomatic, it can last for many years before manifesting itself in the form of type 2 diabetes mellitus, cardiovascular disease, neoplasm, cognitive impairment or dementia, therefore determining enormous social and health care costs. For these reasons, we strongly believe that a screening plan for this pathology should be implemented, in order to identify affected subjects and promptly start them on preventive treatment.

Insulin resistance/hyperinsulinemia as an independent risk factor for the development and worsening of HFpEF. Serafino Fazio MD¹, Valentina Mercurio MD, PhD2, Valeria Fazio MD3, Antonio Ruvolo MD⁴, Flora Affuso MD, PhD⁵. Authors’ Affiliation: ¹ Department of Internal Medicine (retired Professor). Federico II University, Via Sergio Pansini 5. 80135 Naples, Italy. 2 Department of Translational Medical Sciences. Federico II University. Via Sergio Pasini 5. 80135 Naples, Italy. ³ UOC Medicina Interna, Azienda Ospedaliera di Caserta, 81100 Caserta, Italy, ⁴ UOC Cardiologia AORN dei colli PO CTO, Viale Colli Aminei 21, 80100 Naples, Italy. ⁵ Independent researcher, Viale Raffaello 74, 80129 Naples, Italy. Abstract Heart failure (HF) has become a subject of continuous interest since it has been declared new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated, therefore it is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. It should also be underlined that lately, while the prevalence of HF with left ventricular reduced ejection fraction (HFrEF) is slowly decreasing, the incidence of HF with left ventricular preserved ejection fraction (HFpEF) is progressively increasing. In deed, among patients consecutively hospitalized for HF between 1987 and 2001 in a study from the Mayo Clinic Hospitals in Olmsted County, Minnesota, prevalence of HFpEF increased from 38% to 54%. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance/hyperinsulinemia in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, insulin resistance (IR)/hyperinsulinemia (Hyperins) is present in up to 60% of patients with HF and is significantly higher in subjects with HfpEF. In the scientific literature it has been well highlighted that the increased circulating levels of insulin are associated with conditions of insulin resistance are responsible for progressive cardiovascular alterations over the years. In the setting of HFpEF, insulin stimulates the concentric remodeling of the left ventricle with associated diastolic dysfunction, which, coincidentally. Unfortunately, IR/Hyperins, despite being a well-known cardiovascular risk factor, is still not screened in the general population and is not treated as promptly as it should be, and this could at least in part concur in the progressive increase in prevalence of HFpEF in the general adult population. The aim of this manuscript was to review scientific literature that support a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community towards the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in development and worsening of HF, believing that its adequate screening in the general population and appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

Essential (primary) hypertension is defined as such because it does not have an identifiable cause, which is different from secondary hypertension which generally recognizes renal, endocrine, or blood vessel disorders. It is a recognized important risk factor for cardiovascular diseases and it is well known that it is largely more prevalent than secondary hypertension, accounting for 90–95% of affected adults. Therefore, in the vast majority of these cases, we do not recognize the real causes of hypertension, but we treat it without addressing the point that we should be treating hypertension by directly counteracting the cause. Essential hypertension (EH) and insulin resistance (IR) are frequently associated in the same patients, and it should be noted that EH has a comparable and rather high prevalence in adults worldwide, i.e., between 30 and 40%. Also, IR with associated hyperinsulinemia (Hyperin) is an important risk factor for cardiovascular diseases. It can cause hypertension through multiple established pathophysiological mechanisms. IR/Hyperin could be an important cause of most of the cases of essential hypertension. The aim of this Perspective article is to analyze whether the time has come to identify IR as a main contributing cause of essential hypertension. This could produce a better cure for hypertension that is also aimed at treating insulin resistance.