Correction: Insulin resistance/hyperinsulinemia: an important cardiovascular risk factor that has long been underestimated

Serafino Fazio^1*Valentina Mercurio²Loredana Tibullo³Valeria Fazio⁴Flora Affuso⁵

• ¹Federico II University Hospital, Naples, Italy
• ²Azienda Ospedaliera Universitaria Federico II, Naples, Italy
• ³Azienda Sanitaria Locale Caserta, Caserta, Italy
• ⁴Ospedale Santa Maria delle Grazie, Pozzuoli, Italy
• ⁵Independent Researcher, Naples, Italy

The scientific literature consulted and used to write the article was found in PubMed, Scopus, Science Direct, etc. using the following keywords: insulin, insulin signaling, insulin resistance, hyperinsulinemia, cardiovascular risk factors, cardiovascular diseases, cardiovascular system. We selected the studies that explored the association between IR/Hyperins and the cardiovascular system, and those that discussed the possibilities of screening and treatment of IR/Hyperins.Underdstood should be changed to understood. A correction should be made to the section Insulin resistance/Hyperinsulinemia, line 10. The causes of IR are various and not entirely understood: overweight and obesity (particularly visceral); sedentary lifestyle; unbalanced diet in favor of excessive carbohydrate intake; chronic stress; prolonged use of diabetogenic drugs; genetic causes; etc.Micro polycystic ovary syndrome should be changed to polycystic ovary syndrome. A correction should be made to the section Insulin resistance/Hyperinsulinemia, line 19.Diagnosis is easier in subjects with metabolic syndrome and in infertile women with polycystic ovary syndrome, but IR can also be present in subjects that are difficult to suspect, such as in normal weight and thin subjects (7).Carboidrates should be changed to carbohydrates. A correction should be made in the section treatment of IR/Hyperins, line 3.The first thing to do to improve the condition of IR/Hyperins is a radical change in lifestyle by increasing physical activity and reducing daily caloric intake through a balanced diet not rich in carbohydrates.Pre-existig should be changed to pre-existing. A correction should be made in the section Metformin, last line.A few years ago the results of a meta-analysis were published demonstrating how metformin therapy has favorable effects on left ventricular mass (LVM) and EF both in subjects with and without pre-existing cardiovascular disease (61).Fastig insulin should be changed to fasting insulin. A correction should be made in the section berberine, line 16.The results of this study demonstrated that pts treated with berberine had a significant reduction in IR/Hyperins, as documented by reductions in HOMA-IR and fasting insulin levels (39).Cotrasporter2 should be changed to cotransporter2. A correction should be made in the section SGLT2 inhibitors, line 1.Sodium-glucose cotransporter2 inhibitors (SGLT2-i) are a relatively recent class of oral drugs, approved for the treatment of adults with type 2 diabetes and, recently, also for the treatment of HF (50,51).Canaglifozin should be changed to canagliflozin, dapaglifozin to dapagliflozin, empaglifozin to empagliflozin. A correction should be made in the section SGLT2 inhibitors, line 3. They include canagliflozin, dapagliflozin and empagliflozin. A vast scientific literature is now available demonstrating how treatment with SGLT2-i reduces the risk of hospitalization, death from cardiovascular events and all causes of death in patients with HF (52).Metformine should be changed to metformin A correction should be made in the section metformin.Metformin is a long-standing oral antidiabetic, belonging to biguanide class of drugs, which has many scientific demonstrations of effectiveness in reducing IR/Hyperins (57). A literature review study investigated the effects of Metformin on all-cause mortality and the incidence of ageing diseases in diabetic subjects compared to a non-diabetic population, and diabetic subjects treated with therapies different from Metformin. The results of the study highlighted that mortality was significantly reduced in diabetic subjects treated with Metformin, both compared to non-diabetics and diabetics not treated with Metformin. Furthermore, the group of patients treated with Metformin also had a reduction in cancer, compared to non-diabetics, and in cardiovascular diseases, compared to diabetics not taking Metformin (58).Controlled trial should be placebo-controlled trial A correction should be made in the section berberine, line 9.A review and meta-analysis of randomized placebo-controlled trials on berberine has highlighted how it can be a valid alternative, without causing serious adverse reactions, to drugs currently used for cardiovascular prevention (66).Delaglutide should be dulaglutide A correction should be made in the section Glucagon-like peptide 1 receptor agonists.They are administered by subcutaneous injection and are quite expensive drugs. This class of drugs includes semaglutide, albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide. A correction should be made in the section Glucagon-like peptide 1 receptor agonists, line 4.They are administered by subcutaneous injection and are quite expensive drugs. This class of drugs includes semaglutide, albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide.GLP-1 Ras should be GLP-1Ras. A correction should be made in the section Glucagon like peptide-1.Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs not long ago authorized for the treatment of type 2 diabetes and obesity. They are administered Fazio S. et al.by subcutaneous injection and are quite expensive drugs. This class of drugs includes semaglutide, albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide. It seems that they act not only by reducing body weight, but also by acting on mechanisms involved in the determinism of IR/Hyperins, such as, for example, increasing the expression of glucose transporters in insulin-dependent tissues, reducing inflammation and oxidative stress, and modulating lipid metabolism (69, 70).However, although GLP-RAs have actually been shown to improve cardiovascular risk factors such as body weight, blood pressure, LDL cholesterol and triglycerides, and glycemic control, they have been shown to reduce all-cause mortality in patients with type 2 diabetes at high risk of cardiovascular events, but have not reduced cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke and hospitalizations for HF (71,72). Another recent meta-analysis carried out on 54,092 pts from 7 randomized placebo-controlled trials on the use of GLP-1 RAs in subjects with type 2 diabetes, of whom 16% also had a history of HF, demonstrated that these drugs appear to protect the diabetic population from the development of HF, but, in subjects with pre-existing HF, they do not reduce the onset of episodes of HF exacerbation with consequent hospitalization, nor mortality (73). A further recent meta-analysis carried out to verify whether treatment with GLP-1 RAs in subjects with HF, with or without type 2 diabetes, could lead to a reduction in morbidity and mortality compared to placebo, also demonstrated that this therapy did not reduce the number of major adverse cardiovascular events, including cardiovascular mortality or reduction in hospital admissions for HF, and did not lead to an improvement in HF or six-minute walking test (74).In addition, recently, numerous reports of serious adverse events have been published, such as cases of severe pancreatitis. In fact, patients taking either semaglutide or liraglutide had nine times an elevated risk for pancreatitis but, also, they had a very high risk to develop bowel obstruction, and to experience gastroparesis (75). Furthermore, European Medicine Agency published a statement on ongoing review of GLP-1 RAs about the possibility that liraglutide and semaglutide can stimulate suicidal thoughts and self-injury, made by the Icelandic medicines agency (76).Propre screening should be proper screening. A correction should be made in the section concluding remarks, line 4. IR/Hyperins, despite the extensive scientific literature that demonstrates the deleterious effects on cardiovascular system, has never been taken into consideration, with proper screening and treatment as an independent risk factor for the development of cardiovascular disease. Instead, as well highlighted by wide scientific literature, the effects of a chronically increased insulin levels have proved to be particularly harmful at the level of the cardiovascular system, causing important damages to the heart, brain, kidneys, eyes and peripheral vessels. Ita effect should be its effect A correction should be made in the section reference, reference 58.Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and disorders of aging independent of its effect on diabetes control. A systematic review. Aging Res Rev. (2017) 40:31-44. doi: 10.1016/j.arr.2017.08.003 Int J Miol Sci should be Int J Mol Sci A correction should be made at the name of the Journal in the section reference.