Effect of Policaptil Gel Retard on Liver Fat Content and Fibrosis in Adults with Metabolic Syndrome and Type 2 Diabetes: A Non-invasive Approach to MAFLD.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is part of a disease spectrum ranging from steatosis to steatohepatitis (NASH), fibrosis, and cirrhosis, and when associated with metabolic syndrome (MS), and overt diabetes is defined as metabolic NAFLD (MAFLD). Some easily available, inexpensive biomarkers have been validated based on common anthropometric and laboratory parameters, including the Fatty Liver Index (FLI), the Fibrosis (FIB)-4 Score (FIB-4), and the NAFLD Fibrosis Score (NFS). In people with overweight/obesity, MS, and diabetes, the pathogenesis of fatty liver involves parameters known to be positively affected by Policaptil Gel Retard (PGR), a phytocomplex already successfully used in adolescents and adults with MS and type 2 diabetes mellitus (T2DM). This study's primary outcome was to assess PGR's ability to improve indirect validated signs of liver steatosis and fibrosis, i.e., FLI, FIB-4, and NFS Scores; as the secondary outcome, we aimed to confirm PGR's positive effects on anthropometric parameters and lipid levels and to assess any eventually occurring cytolysis liver marker changes in patients with MS/T2DM and MAFLD/NASH. METHODS: In this spontaneous, longitudinal, single-blind, randomized clinical study, 245 outpatients with MS/T2DM were enrolled and randomized to PGR or placebo for 24 weeks. All underwent a low-calorie diet (20-25% less than the calories required to maintain current weight) and were encouraged to intensify physical activity. Fat distribution, liver fat content/fibrosis, and biochemical parameters were evaluated at baseline and after 24 weeks. RESULTS: Our data show for the first time in adults with MAFLD that, when added to lifestyle changes including a hypocaloric diet and intensified physical activity, PGR improves lipid and glucose metabolism-related parameters, including insulin-resistance, and significantly reduces not only visceral fat but also liver fat content and related liver fibrosis severity. The prevalence of subjects with severe steatosis (FLI > 60) significantly decreased from 95.08 to 47.53% (p < 0.001) only in the treatment group, which also displayed a significantly decreased prevalence of medium-severe cases (F3-F4) from 83.62% to 52.35% (p < 0.001) and a markedly increased prevalence of low degree cases (F0-F1) from 9.01 to 42.15% (p < 0.001). CONCLUSIONS: The effect of PGR is related to a reduction in the post-meal blood glucose and insulin peaks. As glucose absorption (GA) directly regulates pancreatic insulin release, the attenuated insulin response is likely due to delayed GA with decreased body weight, visceral fat, and cardiovascular risk. Also, an effect on the intestinal microbiota, already documented in the animal model, cannot be excluded, especially considering the reported PGR-related shift from the Firmicutes, notoriously responsible for increased lipid gut absorption, to the Bacteroides phylum.

Protective Effects of Home T2DM Treatment with Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Co-transporter-2 Inhibitors Against Intensive Care Unit Admission and Mortality in the Acute Phase of the COVID-19 Pandemic: A Retrospective Observational Study in Italy.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a relevant risk factor for severe forms of COVID-19 (SARS coronavrus 2 [SARS-CoV-2] disease 2019), and calls for caution because of the high prevalence of T2DM worldwide and the high mortality rates observed in patients with T2DM who are infected with SARS-CoV-2. People with T2DM often take dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1ras), or sodium-glucose co-transporter-2 inhibitors (SGLT-2is), all of which have clear anti-inflammatory effects. The study aimed to compare (i) the severity and duration of hospital stay between patients with T2DM categorized by pre-hospitalization drug class utilization and (ii) the COVID-19-related death rates of those three groups. METHODS: We designed an observational, retrospective, multi-center, population-based study and extracted the hospital admission data from the health care records of 1916 T2DM patients over 18 years old who were previously on GLP-1ra, SGLT-2i, or DPP-4i monotherapy and were hospitalized for COVID-19 (diagnosis based on ICD.9/10 codes) between January 2020 and December 2021 in 14 hospitals throughout Italy. We analyzed general data, pre-admission treatment schedules, date of admission or transfer to the intensive care unit (ICU) (i.e., the index date; taken as a marker of increased COVID-19 disease severity), and death (if it had occurred). Statistics analyzed the impact of drug classes on in-hospital mortality using propensity score logistic regressions for (i) those admitted to intensive care and (ii) those not admitted to intensive care, with a random match procedure used to generate a 1:1 comparison without diabetes cohort replacement for each drug therapy group by applying the nearest neighbor method. After propensity score matching, we checked the balance achieved across selected variables if a balance was ever achieved. We then used propensity score matching between the three drug classes to assemble a sample in which each patient receiving an SGLT-2i was matched to one on a GLP-1ra, and each patient on a DPP-4i was matched to one on a GLP-1ra, adjusting for covariates. We finally used GLP-1ras as references in the logistic regression. RESULTS: The overall mortality rate (MR) of the patients was 14.29%. The MR in patients with COVID was 53.62%, and it was as high as 42.42% in the case of associated T2DM, regardless of any glucose-lowering therapy. In those on DPP-4is, there was excess mortality; in those treated with GLP-1ras and SGLT-2is, the death rate was significantly lower, i.e., almost a quarter of the overall mortality observed in COVID-19 patients with T2DM. Indeed, the odds ratio (OR) in the logistic regression resulted in an extremely high risk of in-hospital death in individuals previously treated with DPP-4is [incidence rate (IR) 4.02, 95% confidence interval (CI) 2.2-5.7) and only a slight, nonsignificantly higher risk in those previously treated with SGLT-2is (IR 1.42, 95% CI 0.6-2.1) compared to those on GLP-1ras. Moreover, the longer the stay, the higher the death rate, which ranged from 22.3% for ≤ 3-day stays to 40.3% for 4- to 14-day stays (p < 0.01 vs. the former) and 77.4% for over-14-day stays (p < 0.001 vs. both the others). DISCUSSION: Our data do not support a protective role of DPP-4is; indeed, this role has already been questioned due to previous observations. However, the data do show a strong protective effect of SGLT-2is and GLP-1ras. Beyond lowering circulating glucose levels, those two drug classes were found to exert marked anti-phlogistic effects: SGLT-2is increased adiponectin and reduced urate, leptin, and insulin concentrations, thus positively affecting overall low-grade inflammation, and GLP-1ras may also greatly help at the lung tissue level, meaning that their extra-glycemic effects extend well beyond those acknowledged in the cardiovascular and renal fields. CONCLUSIONS: The aforedescribed observational clinical data relating to a population of Italian inpatients with T2DM suggest that GLP-1ras and SGLT-2is can be considered antidiabetic drugs of choice against COVID-19, and might even prove beneficial in the event of any upcoming pandemic that has life-threatening effects on the pulmonary and cardiovascular systems.

Lipohypertrophy and Insulin: An Update From the Diabetes Technology Society.

Lipohypertrophy is a common skin complication associated with insulin-treated diabetes. The impact of lipohypertrophy as a contributing factor to suboptimal glycemic control, glucose variability, and hypoglycemia is often under-recognized by health care professionals. In a recent Webinar on April 26, 2023, Diabetes Technology Society asked international experts to provide updates on the latest knowledge related to lipohypertrophy for practicing clinicians and educators, researchers, and industries involved in insulin delivery. A recording of the Webinar is freely available on the Diabetes Technology Society Web site (https://www.diabetestechnology.org/).

Lipohypertrophy and Insulin: An Old Dog That Needs New Tricks.

OBJECTIVE: To review the current status of practical knowledge related to insulin-associated lipohypertrophy (LH) - an accumulation of fatty subcutaneous nodules commonly caused by repeated injections and/or infusions of insulin into the same site. METHODS: Review of published literature with additional contributions from leading multidisciplinary experts with the emphasis on clinical aspects including pathophysiology, clinical and economic consequences, diagnosis, prevention and treatment. RESULTS: LH is the most common dermatologic complication of insulin therapy. Risk factors for the development of lipohypertrophy include repeated delivery of large amounts of insulin into the same location over time, repeated injection trauma to the skin and subcutaneous tissue, and multiple injections using the same needle. Subcutaneous insulin injection in skin areas with lipohypertrophy is associated with reduced pain; however, this problem can interfere with insulin absorption, thereby increasing the likelihood of glucose variability, hypo- and hyperglycemia when a site is changed. Modern visualization technology of the subcutaneous space with ultrasound can demonstrate lipohypertrophy early in the course of its development. CONCLUSIONS: The physiological and psychological consequences of developing insulin lipohypertrophy can be prevented and treated with education focusing on insulin injection techniques.

Why Do So Many People with Type 2 Diabetes Who Take Insulin Have Lipohypertrophy? Fate or Educational Deficiencies?

INTRODUCTION: Cutaneous lipohypertrophy (LH) is a thickened, "rubbery" lesion in the subcutaneous tissue following multiple injections performed at the same site, i.e., an incorrect injection technique. It is widespread, averaging 47% of insulin patients worldwide, and has severe direct and indirect consequences. Direct consequences consist mainly of poor metabolic control and frequent hypoglycemic events (HYPOs), and indirect ones of markedly increased healthcare costs related to hospital access due to acute events and long-term disease complications. This observation also holds for Italy, despite the National Health System organization expecting every patient with diabetes to undergo a series of visits by different care team members, each performing a specific treatment/education task. Indeed, the recent literature points to poor awareness of LH relevance and metabolic consequences among doctors from general and diabetic hospital wards, with educational deficiencies on correct injection practice in nurses too. The aim was to establish if, to what extent, and by whom they had received training on correct insulin injection techniques, and how many initially received notions had persisted over time. METHODS: We investigated the possible causes of such a failure from the point of view of 1160 insulin-requiring subjects with type 2 diabetes (T2DM), reporting for the first time to specialized diabetic structures through a validated questionnaire and, in the same patients, we searched for LH by inspection/palpation according to international guidelines, further confirmed by ultrasound scans. We then analyzed differences in education and injecting behavior between subjects classified as LH+ or LH- depending on the presence or absence of LH lesions. RESULTS: We documented significant educational gaps, with 50% of patients failing to refer to healthcare professionals and relying on their peers with diabetes, thought to be more experienced in 15% of the cases. Seventy-five percent of LH- patients received education from healthcare providers, while 90% of LH+ learned from another patient or could not remember how they knew, and 68% of LH+ versus 52% of LH- (p < 0.01) patients had failed to receive training on injection techniques by healthcare providers. All of this enabled the most disabling features of diabetes from the very beginning of the disease history. CONCLUSIONS: This study documents, from the patients' point of view, that educational gaps are significant and that, even in initially trained subjects, education on correct injection techniques has a fleeting effect if not regularly recalled. Therefore, to rehabilitate LH+ patients as soon as possible and prevent LH- patients from inadvertently slipping into the other group, there is an urgent need to educate doctors and nurses repeatedly on the importance of correctly injecting insulin to improve patients' knowledge and skills.

Heart Failure with Preserved Ejection Fraction and Obstructive Sleep Apnea: A Novel Paradigm for Additional Cardiovascular Benefit of SGLT2 Inhibitors in Subjects With or Without Type 2 Diabetes.

After examining the complex interplay between heart failure (HF) in its various clinical forms, metabolic disorders like nonalcoholic fatty liver disease (NAFLD), and obstructive sleep apnea (OSA) syndrome, in this mini-review we described possible favorable effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on HF with preserved (i.e., ≥ 50%) ejection fraction (HFpEF) through enhanced cardiorenal function and visceral-subcutaneous body fat redistribution. In greater detail, on the basis of pathophysiological mechanisms underlying OSA onset and the direct positive SGLT2i effect on renal function benefiting chronic kidney disease, we emphasized the promising role of SGLT2is in prevention, rehabilitation, and treatment of patients with OSA regardless of coexisting type 2 diabetes (T2DM). Indeed, SGLT2is enhance lipolysis and fatty acid beta-oxidation. These phenomena might prevent OSA by reducing the size of visceral and subcutaneous adipose tissue and, as proven in humans and animals with T2DM, counteract NAFLD onset and progression. The aforementioned mechanisms may represent an additional SGLT2i cardioprotective effect in terms of HFpEF prevention in patients with OSA, whose NAFLD prevalence is estimated to be over 50%.

The Economic Burden of Insulin Injection-Induced Lipohypertophy. Role of Education: The ISTERP-3 Study.

INTRODUCTION: The history of insulin-induced skin lipohypertrophy (LH) runs parallel to that of insulin's 100 years, and an average of 47% of insulin-treated patients still suffer from it today. The metabolic and economic effects of LH are significant, with hypoglycemia being the most striking. The objective of the study was to perform a 52-week follow-up of 713 insulin-treated patients with type 2 diabetes (T2DM) and LH to detect any differences in the occurrence of hypoglycemic events (HYPOs) and related healthcare costs as well as in LH rates and injection habits between an intensive education intervention group (IG) and control group (CG) provided with a single educational session at the starting point. METHODS: All participants were trained in accurately self-monitoring blood glucose and recording all HYPOs for 6 months, which allowed baseline recordings before they were randomized into the IG, comprising 395 insulin-treated subjects undergoing repeated, structured multimodal education on correct injection techniques as a longstanding behavioral rehabilitation strategy, and the CG, comprising 318 subjects receiving the same structured, multimodal educational session, but only initially. RESULTS: Changes in LH rate and size and in performance were large in the IG and only slight and transient in the CG. A striking difference in the rate of decrease of HYPOs was also apparent between groups. Indeed, estimated costs of health interventions for severe and symptomatic HYPOs, which were on the order of €70,000 and €9300, respectively, in the two groups at baseline decreased by 5.9 times and 13.7 times, respectively, at the end of follow-up in the IG and by only approximately half in the CG. Full details of the changes occurring as a result of intensive education are provided in the text. CONCLUSIONS: The effect of only initial education in the CG was not significant, thus providing evidence of the virtual worthlessness of a single training session on injection techniques, typical of worldwide daily clinical practice, and easily explaining the extremely high prevalence of LH in insulin-treated patients. Conversely, highly positive effects on LH prevalence and size as well as costs expected from decreased HYPO rate were obtained in the IG. To our knowledge, ours is the first 18-month randomized trial in the field. If our experimental model were to be used as an effective, longstanding behavioral rehabilitation strategy and therefore adapted to real-world settings universally, LH prevalence and costs related to their clinical consequences would be drastically reduced. However, only with a strong, relentless commitment of universities, scientific societies, and patient associations can we achieve this ambitious goal, which would provide great institutional savings and improved quality of life for people with diabetes.

Kidney and lung in pathology: mechanisms and clinical implications.

There is a close, physiological, relationship between kidney and lung that begin in the fetal age, and is aimed to keep homeostatic balance in the body. From a pathological point of view, the kidneys could be damaged by inflammatory mediators or by immune-mediated factors linked to a primary lung disease or, conversely, it could be the kidney disease that causes lung damage. Non-immunological mechanisms are frequently involved in renal and pulmonary diseases, as observed in chronic conditions. This crosstalk have clinical and therapeutic consequences. This review aims to describe the pulmonary-renal link in physiology and in pathological conditions.

The Durability of an Intensive, Structured Education-Based Rehabilitation Protocol for Best Insulin Injection Practice: The ISTERP-2 Study.

INTRODUCTION: Studies on the durability of an intensive, structured education protocol on best insulin injection practice are missing for people with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the durability of an intensive, structured education-based rehabilitation protocol on best insulin injection practice in well-trained subjects from our previous intensive, multimedia intervention study registered as the ISTERP-1 study. A total of 158 subjects with T2DM from the well-trained group of the 6-month-long ISTERP-1 study, all of whom had successfully attained lower glucose levels compared to baseline levels with lower daily insulin doses and with less frequent and severe hypoglycemic episodes, participated in the present investigation involving an additional 6-month follow-up period, called the ISTERP-2 study. METHODS: Participants were randomized into an intervention group and a control group, depending on whether they were provided or not provided with further education refresher courses for 6 months. At the end of the 6 months, the two groups were compared in terms of injection habits, daily insulin dose requirement, number of severe or symptomatic hypoglycemic events, and glycated hemoglobin (HbA1c) levels. RESULTS: Despite being virtually superimposable at baseline, the two groups behaved quite differently during the follow-up. The within-group analysis of observed parameters showed that the subjects in the intervention group maintained and even improved the good behavioral results learned during the ISTERP-1 study by further reducing both the rate of injection technique errors (p < 0.001) and size of lipohypertrophic lesions at injection sites (p < 0.02). Conversely, those in the control group progressively abandoned best practice, except for the use of ice-cold insulin and, consequently, had significantly higher HbA1c levels and daily insulin dose requirements at the end of the follow-up than at baseline (p < 0.05). In addition, as expected from all the above, the rate of hypoglycemic episodes also decreased in the intervention group (p < 0.05), resulting in a significant difference between groups after 6 months (p < 0.02). CONCLUSION: Our data provide evidence that intensive, structured education refresher courses have no outstanding durability, so that repeated refresher courses, at least at 6-month intervals, are needed to have positive effects on people with T2DM, contributing not only to prevention but also to long-term rehabilitation. TRIAL REGISTRATION: Trial Registration no. 118 bis/15.04.2018.

Possible Preventative/Rehabilitative Role of Gliflozins in OSA and T2DM. A Systematic Literature Review-Based Hypothesis.

Obstructive sleep apnoea (OSA) is characterized by frequent apnoea episodes during sleep due to upper airway obstruction. The present review summarizes current knowledge on inter-relationships between OSA and type 2 diabetes mellitus (T2DM) and suggests the former as a possible target for sodium-glucose co-transporter-2 inhibitors (SGLT-2i). Based on pathophysiological mechanisms underlying OSA onset and renal SGLT-2 effects, we suggest that SGLT-2i indications might expand beyond current ones, including glucose, lipids, uric acid, blood pressure, and body weight control as well as chronic heart failure and kidney disease prevention.

Hundred-year experience with insulin and lipohypertrophy: An unresolved issue.

In the article recently published in Diab Res Clin Pract (1), we described one of the most exciting paths in the history of medicine from the perspective of diabetologists and people with type 1 diabetes. Such a history lasted 100 years, from the discovery of insulin to the most technologically advanced technologies aimed at making treatment as close to physiology and user-friendly as possible. Indeed, we are luckier than others because, by living in Italy and the USA, respectively, we have access to miniaturized and computerized insulin delivery systems, but this is not the case worldwide. Due to that, while receiving many favorable comments from colleagues and friends, we were encouraged to further expand on the issue and go deeper into insulin injection technique.

Insulin-induced skin lipohypertrophies: A neglected cause of hypoglycemia in dialysed individuals with diabetes.

BACKGROUND: Diabetes mellitus (DM) is the leading cause of end-stage renal disease and 50% of dialysis patients are insulin-treated. AIM: to search for unexplained hypoglycemia (HYPO). METHODS: identify a possible cause of HYPO due to altered insulin absorption. RESULTS: insulin injected into subcutaneous lipo-hypertrophy (LH) nodules leads to unpredictable HYPOS. CONCLUSION: looking for LH systematically and training patients to the best injection technique are new challenges for nephrologists to reduce HYPO and emergency hospitalization rates, thus sparing healthcare resources and improving the quality of life of insulin-treated dialysis patients.

Role of Structured Education in Reducing Lypodistrophy and its Metabolic Complications in Insulin-Treated People with Type 2 Diabetes: A Randomized Multicenter Case-Control Study.

INTRODUCTION: It is essential to use the correct injection technique (IT) to avoid skin complications such as lipohypertrophy (LH), local inflammation, bruising, and consequent repeated unexplained hypoglycemia episodes (hypos) as well as high HbA1c (glycated hemoglobin) levels, glycemic variability (GV), and insulin doses. Structured education plays a prominent role in injection technique improvement. The aim was to assess the ability of structured education to reduce (i) GV and hypos, (ii) HbA1c levels, (iii) insulin daily doses, and (iv) overall healthcare-related costs in outpatients with T2DM who were erroneously injecting insulin into LH. METHODS: 318 patients aged 19-75 years who had been diagnosed with T2DM for at least 5 years, were being treated with insulin, were routinely followed by a private network of healthcare centers, and who had easily seen and palpable LH nodules were included in the study. At the beginning of the 6-month run-in period (T-6), all patients were trained to perform structured self-monitoring of blood glucose and to monitor symptomatic and severe hypos (SyHs and SeHs, respectively). After that (at T0), the patients were randomly and equally divided into an intervention group who received appropriate IT education (IG) and a control group (CG), and were followed up for six months (until T+6). Healthcare cost calculations (including resource utilization, loss of productivity, and more) were carried out based on the average NHS reimbursement price list. RESULTS: Baseline characteristics were the same for both groups. During follow-up, the intra-LH injection rate for the CG progressively decreased to 59.9% (p < 0.001), a much smaller decrease than seen for the IG (1.9%, p < 0.001). Only the IG presented significant decreases in HbA1c (8.2 ± 1.2% vs. 6.2 ± 0.9%; p < 0.01), GV (247 ± 61 mg/dl vs. 142 ± 31 mg/dl; p < 0.01), insulin requirement (- 20.7%, p < 0.001), and SeH and SyH prevalence (which dropped dramatically from 16.4 to 0.6% and from 83.7 to 7.6%, respectively; p < 0.001). In the IG group only, costs-including those due to the reduced insulin requirement-decreased significantly, especially those relating to SeHs and SyHs, which dropped to €25.8 and €602.5, respectively (p < 0.001). CONCLUSION: Within a 6-month observation period, intensive structured education yielded consistently improved metabolic results and led to sharp decreases in the hypo rate and the insulin requirement. These improvements resulted in a parallel drop in overall healthcare costs, representing a tremendous economic advantage for the NHS. These positive results should encourage institutions to resolve the apparently intractable problem of LH by financially incentivizing healthcare teams to provide patients with intensive structured education on proper injection technique. TRIAL REGISTRATION: Trial registration no. 118/15.04.2018, approved by the Scientific and Ethics Committee of Campania University "Luigi Vanvitelli," Naples, Italy, and by the institutional review board (IRB Min. no. 9926 dated 05.05.2018).

Bruising: A Neglected, Though Patient-Relevant Complication of Insulin Injections Coming to Light from a Real-Life Nationwide Survey.

INTRODUCTION: Despite the availability of sophisticated devices and suitable recommendations on how to best perform insulin injections, lipohypertrophy (LH) and bruising (BR) frequently occur as a consequence of improper injection technique. AIM: The purpose of this nationwide survey was to check literature-reported LH risk factors or consequences for any association with BR METHOD: This was a cross-sectional, observational, multicenter study based on the identification of skin lesions at all patient-reported insulin injection sites in 790 subjects with diabetes. General and injection habit-related elements were investigated as possible BR risk factors. RESULTS: While confirming the close relationship existing between LH and a full series of factors including missed injection site rotation, needle reuse, long-standing insulin treatment, frequent hypoglycemic events (hypos), and great glycemic variability (GV), the observed data could find no such association with BR, which anyhow came with high HbA1c levels, missed injection site rotation, and long-standing insulin treatment. CONCLUSION: BR most likely depends on the patient's habit of pressing the injection pen hard onto the skin. Despite being worrisome and affecting quality of life, BR seems to represent a preliminary stage of LH but does not affect the rate of hypos and GV. TRIAL REGISTRATION: 207/19.09.2017.

Lipohypertrophy in Elderly Insulin-Treated Patients With Type 2 Diabetes.

BACKGROUND: The number of older adults with insulin-treated diabetes mellitus (DM) is steadily increasing worldwide. Errors in the insulin injection technique can lead to skin lipohypertrophy (LH), which is the accumulation of fat cells and fibrin in the subcutaneous tissue. While lipohypertrophic lesions/nodules (LHs) due to incorrect insulin injection techniques are very common, they are often flat and hardly visible and thus require thorough deep palpation examination and ultrasonography (US) for detection. Detection is crucial because such lesions may eventually result in poor diabetes control due to their association with unpredictable insulin release patterns. Skin undergoes fundamental structural changes with aging, possibly increasing the risk for LH. We have therefore investigated the effect of age on the prevalence of LHs and on factors potentially associated with such lesions. METHODS: A total of 1227 insulin-treated outpatients with type 2 DM (T2DM) referred to our diabetes centers were consecutively enrolled in the study. These patients underwent a thorough clinical and US evaluation of the skin at injection sites, as previously described, with up to 95% concordance betweenthe clinical and US screening techniques. Of these 1227 patients, 718 (59%) had LH (LH+) and 509 (41%) were LH-free (LH-). These patients were then assigned to two age class groups (≤ 65 years and > 65 years), and several clinical features, diabetes complication rates, and injection habits were investigated. RESULTS: Comparison of the two age subgroups revealed that 396 (48%) and 322 (79%) patients in the younger and older groups, respectively, had LHs (p < 0.001). Compared to the younger subgroup, the older subgroup displayed a higher LH rate in the abdomen (52.9 vs. 38.3%; p < 0.01) and a lower rate in the arms (25.4 vs. 35.8%; p < 0.05), thighs (26.7 vs. 33.4%; p < 0.05), and buttocks (4.9 vs. 26.2%; p < 0.01). In older subjects, the most relevant parameters were: habit of injecting insulin into LH nodules (56 vs. 47% [younger subjects]; p < 0.01), rate of post-injection leakage of insulin from injection site (drop-leaking rate; 47 vs. 39% [younger subjects]; p < 0.05), and rate of painful injections (5 vs. 16% [younger subjects]; p < 0.001). Multivariate analysis showed a stronger association between LH and poor habits, as well as between several clinical parameters, among which the most relevant were hypoglycemic events and glycemic variability. DISCUSSION: The higher rate of post-injection drop-leaking and pain-free injections might find an explanation in skin changes typically observed in older adults, including lower thickness, vascularity and elasticity, and a more prominent fibrous texture, all of which negatively affect tissue distensibility. Consequently, in addition to the well-known association between aging skin impaired drug absorption rate, aging skin displays a progressively decreasing ability to accommodate large volumes of insulin-containing fluid. CONCLUSIONS: The strong association between LH rate and hypoglycemic events plus glycemic variability suggests the need (1) to take specific actions to prevent and control the high risk of acute cardiovascular events expected to occur in older subjects in the case of hypoglycemic events, and (2) to identify suitable strategies to fulfill the difficult task of performing effective educational programs specifically targeted to the elderly. TRIAL REGISTRATION: Trial registration number 172-11:12.2019, Scientific and Ethical Committee of Campania University "Luigi Vanvitelli", Naples, Italy).