Trends and cyclic variation in the incidence of childhood type 1 diabetes in two Italian regions over 33 years and during the COVID-19 pandemic.

AIM: There is conflicting evidence about the impact of the COVID-19 pandemic on the incidence of type 1 diabetes. Here, we analysed long-term trends in the incidence of type 1 diabetes in Italian children and adolescents from 1989 to 2019 and compared the incidence observed during the COVID-19 pandemic with that estimated from long-term data. MATERIALS AND METHODS: This was a population-based incidence study using longitudinal data from two diabetes registries in mainland Italy. Trends in the incidence of type 1 diabetes from 1 January 1989 to 31 December 2019 were estimated using Poisson and segmented regression models. RESULTS: There was a significant increasing trend in the incidence of type 1 diabetes of 3.6% per year [95% confidence interval (CI): 2.4-4.8] between 1989 and 2003, a breakpoint in 2003, and then a constant incidence until 2019 (0.5%, 95% CI: -1.3 to 2.4). There was a significant 4-year cycle in incidence over the entire study period. The rate observed in 2021 (26.7, 95% CI: 23.0-30.9) was significantly higher than expected (19.5, 95% CI: 17.6-21.4; p = .010). CONCLUSION: Long-term incidence analysis showed an unexpected increase in new cases of type 1 diabetes in 2021. The incidence of type 1 diabetes now needs continuous monitoring using population registries to understand better the impact of COVID-19 on new-onset type 1 diabetes in children.

Hepatic fibrosis of any origin in a large population of type 2 diabetes patients.

BACKGROUND AND AIMS: Excess morbidity and mortality from chronic liver disease in type 2 diabetes (T2DM) is recognized; however, the clinical features associated with liver fibrosis (LF) of any origin are poorly known. Metabolic status and/or coexisting complications over time may play a role. METHODS AND RESULTS: We interrogated the database of the diabetes unit network of Piedmont (Italy) (71,285 T2DM patients) and calculated a fibrosis-4 score (FIB-4) from data recorded between 2006 and 2019. Comorbidities were obtained by linkage with hospital data. The study population was subdivided by aetiology of LF (alcoholic, viral, metabolic). Associations between upper level of FIB-4 and demographic and clinical variables were evaluated separately for each group using robust Poisson models and presented as prevalence ratios. Nearly one-quarter (24%) of T2DM patients had some form of LF: viral (0.44%) and alcoholic (0.53%) forms were far less frequent than metabolic ones (22.7%). Only 1 out of 5 of these patients had a history of known cirrhosis. Age, male sex, duration of diabetes, coronary disease, hyperuricemia, renal failure, and features of liver failure (e.g., lower body-mass index, lipid and HbA1c levels) were positively associated with metabolic LF. More intensive treatments with insulin and segretagogue emerged as a significant predictive indicators of LF of metabolic origin. CONCLUSION: A sizeable proportion of T2DM patients has some degree of LF, mainly of metabolic origin and often undiagnosed. There is a need to clarify whether the link between insulin therapy and advanced LF is causal or not.

Effects of Dipeptidyl Peptidase-4 Inhibitor Linagliptin on Left Ventricular Dysfunction in Patients with Type 2 Diabetes and Concentric Left Ventricular Geometry (the DYDA 2™ Trial). Rationale, Design, and Baseline Characteristics of the Study Population.

PURPOSE: A multicentre, randomized, double-blind, placebo-controlled, parallel-group study aimed to define the potential positive effect of dipeptidyl peptidase-4 inhibition on left ventricular systolic function (LVSF) beyond glycemic control in type 2 diabetes mellitus (T2DM) (DYDA 2™ trial). METHODS: Individuals with fairly controlled T2DM and asymptomatic impaired LVSF were randomized in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their stable diabetes therapy. Eligibility criteria were age ≥ 40 years, history of T2DM with a duration of at least 6 months, HbA1c ≤ 8.0% (≤ 64 mmol/mol), no history or clinical signs/symptoms of cardiac disease, evidence at baseline echocardiography of concentric LV geometry (relative wall thickness ≥ 0.42), and impaired LVSF defined as midwall fractional shortening (MFS) ≤ 15%. The primary end-point was the modification from baseline to 48 weeks of MFS. As an exploratory analysis, significant changes in LV global longitudinal strain and global circumferential strain, measured by speckle tracking echocardiography, were also considered. Secondary objectives were changes in diastolic and/or in systolic longitudinal function as measured by tissue Doppler. RESULTS: A total of 188 patients were enrolled. They were predominantly males, mildly obese, with typical insulin-resistance co-morbidities such as hypertension and dyslipidemia. Mean relative wall thickness was 0.51 ± 0.09 and mean MFS 13.3% ± 2.5. CONCLUSIONS: DYDA 2 is the first randomized, double-blind, placebo-controlled trial to explore the effect of a dipeptidyl peptidase-4 inhibitor on LVSF in T2DM patients in primary prevention regardless of glycemic control. The main characteristics of the enrolled population are reported. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT02851745.

Impact of severe and symptomatic hypoglycemia on quality of life and fear of hypoglycemia in type 1 and type 2 diabetes. Results of the Hypos-1 observational study.

BACKGROUND AND AIMS: Hypoglycemia represents a relevant burden in people with diabetes. Consequences of hypoglycemia/fear of hypoglycemia on quality of life (QoL) and behaviors of patients with T1DM and T2DM were assessed. METHODS AND RESULTS: HYPOS-1 was an observational retrospective study. Fear of hypoglycemia (Fear of Hypoglycemia Questionnaire, FHQ), general health status (visual analog scale of EuroQol questionnaire, EQ5D-VAS) psychological well-being (WHO-5 well being index, WHO-5), diabetes related distress (Problem Areas in Diabetes 5, PAID-5), and corrective/preventive behaviors following hypoglycemia were compared between people with and without previous experience of severe and symptomatic hypoglycemia and by tertiles of FHQ scores. A multivariate analysis was performed to identify factors associated with the likelihood of being in the third tertile of FHQ score. Overall, 2229 patients were involved. Severe hypoglycemia had statistically significant and clinically relevant (measured as effect sizes) negative impact on EQ5D-VAS, WHO-5, PAID-5, and FHQ both in T1DM and T2DM. In T2DM, symptomatic episodes had similar impact of severe hypoglycemia. Moving from the first to the third FHQ tertile, lower scores of EQ-5D VAS and WHO-5, and higher levels of PAID-5 were found. Patients in the third tertile performed more frequently corrective/preventive actions that negatively impact on metabolic control. Previous hypoglycemia, insulin treatment, female gender, age, and school education were the independent factors associated with increased likelihood to be in the third tertile. CONCLUSION: Not only severe but also symptomatic hypoglycemia negatively affect patient QoL, especially in T2DM. Addressing fear of hypoglycemia should be a goal of diabetes education.

Beta cell stress in a 4-year follow-up of patients with type 2 diabetes: A longitudinal analysis of the BetaDecline Study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a progressive deterioration in beta cell function and loss of glycaemic control. Clinical predictors of beta cell failure are needed to guide appropriate therapy. METHODS: A prospective evaluation of a large set of potential predictors of beta cell stress, measured as change in the proinsulin/insulin (PI/I) ratio, was conducted in a cohort of 235 outpatients with T2DM on stable treatment with oral hypoglycaemic agents or diet followed up for ~4 years (median value 3.9 years; interquartile range 3.8-4.1 years). RESULTS: Overall, metabolic control deteriorated over time, with a significant increase in glycated haemoglobin (HbA1c; P < .0001), proinsulin (P < .0001), and PI/I ratio (P = .001), without significant changes in the homeostatic model assessment of insulin resistance. Multivariate regression analysis showed that for each 1% (10.9 mmol/mol) increase from baseline in HbA1c, the risk of beta cell stress increased by 3.8 times; for each 1% (10.9 mmol/mol) incremental increase in HbA1c during the study, risk of beta cell stress increased by 2.25 times that at baseline. By contrast, baseline anthropometric and clinical variables, lipid profile, inflammatory markers (PCR, IL-6), non-esterified fatty acids, and current therapies did not independently influence PI/I ratio variation during follow-up. CONCLUSIONS: In this cohort of patients with T2DM, beta cell function progressively deteriorated despite current therapies. Among a large set of clinical and biochemical predictors, only baseline HbA1c levels and their deterioration overtime were associated with higher beta cell stress over time.

Apparent Treatment Resistant Hypertension, Blood Pressure Control and the Progression of Chronic Kidney Disease in Patients with Type 2 Diabetes.

BACKGROUND/AIMS: Apparent treatment resistant hypertension (aTRH) is highly prevalent in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The impact of aTRH and achievement of recommended blood pressure (BP) values on the rate of glomerular filtration rate (eGFR) loss in CKD patients is poorly known. To assess the role of aTRH and time-updated BP control (BPC) on the progression of CKD in patients with T2D and hypertension (HT) in real life clinical practice. METHODS: Clinical records from a total of 2,778 diabetic patients with HT and stage 3 CKD (i.e. baseline eGFR values between 30 and 60 ml/min) and regular visits during a four-year follow-up were analyzed. The association between BPC (i.e. 75% of visits with BP <140/90 mmHg) and eGFR loss (i.e. a >30% reduction from baseline) or worsening of albuminuria status over time was assessed. RESULTS: At baseline 33% of patients had aTRH. Over the 4-year follow-up, 20% had a >30% eGFR reduction. Patients with aTRH had an increased risk of eGFR loss >30% (OR 1.31; P<0.007). In patients with aTRH, BPC was associated with a 79% (P=0.029) greater risk of eGFR reduction despite a 58% (P=0.001) lower risk of albuminuria status worsening. In non-aTRH, no association was found between BPC and renal outcome. CONCLUSION: In patients with stage 3 CKD the presence of aTRH entails a faster loss of eGFR. More effective prevention of aTRH should be implemented as this condition is associated with a burden of risk not modifiable by tight BP reduction.

Diabetic kidney disease in the elderly: prevalence and clinical correlates.

BACKGROUND: Diabetic kidney disease (DKD) is a major burden in elderly patients with type 2 diabetes (T2DM). Low estimated glomerular filtration rate (eGFR+, < 60 mL/min/1.73 m2) and albuminuria (Alb+) are essential for the diagnosis of DKD, but their association with clinical variables and quality of care may be influenced by ageing. METHODS: Here we investigated the association of clinical variables and quality of care measures with eGFR+ and Alb+ in 157,595 T2DM individuals participating to the Italian Association of Clinical Diabetologists (AMD) Annals Initiative, stratified by age. RESULTS: The prevalence of eGFR+ and Alb+ increased with ageing, although this increment was more pronounced for low eGFR. Irrespective of age, both the eGFR+ and Alb + groups had the worst risk factors profile when compared to subjects without renal disease, showing a higher prevalence of out-of target values of HbA1c, BMI, triglycerides, HDL-C, blood pressure and more complex cardiovascular (CVD) and anti-diabetic therapies, including a larger use of insulin In all age groups, these associations differed according to the specific renal outcome examined: male sex and smoking were positively associated with Alb+ and negatively with eGFR+; age and anti-hypertensive therapies were more strongly associated with eGFR+, glucose control with Alb+, whereas BMI, and lipid-related variables with both abnormalities. All these associations were attenuated in the older (> 75 years) as compared to the younger groups (< 65 years; 65-75 years), and they were confirmed by multivariate analysis. Notably, Q-score values < 15, indicating a low quality of care, were strongly associated with Alb+ (OR 8.54; P < 0.001), but not with eGFR+. CONCLUSIONS: In T2DM patients, the prevalence of both eGFR and Albuminuria increase with age. DKD is associated with poor cardiovascular risk profile and a lower quality of care, although these associations are influenced by the type of renal abnormality and by ageing. These data indicate that clinical surveillance of DKD should not be unerestimated in old T2DM patients.

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes.

BACKGROUND: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. METHODS: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. RESULTS: The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage ≥3 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. CONCLUSIONS: Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening.

Occurrence over time and regression of nonalcoholic fatty liver disease in type 2 diabetes.

BACKGROUND: This analysis was aimed to assess the incidence, regression, and correlated factors of nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes, which are poorly known. METHODS: Nonalcoholic fatty liver disease (defined as fatty liver index [FLI] score ≥ 60) in patients with type 2 diabetes, and related factors was investigated in a nationwide database containing information from the Italian network of diabetes clinics. A 10% variation of FLI was the cut-off considered in the analyses of a cohort of 5030 patients, which was separately conducted for those who developed, maintained, or recovered from FLI-assessed NAFLD (FLI-NAFLD) over a 3-year period. RESULTS: At baseline, FLI-NAFLD was diagnosed in 61.3% of patients. Within the 3-year study period, FLI-NAFLD occurred in 313 patients and remitted in 410. The FLI score remained unchanged in 4307. Body-mass index (odds ratio, 1.45 95%; confidence interval, 1.35-1.55), abdominal obesity (2.11; 1.64-2.72), low HDL cholesterol levels (1.38; 1.02-1.87), and triglycerides (1.20; 1.12-1.28) all emerged as notable negative prognostic factors for the development or maintenance of FLI-NAFLD. The regression rate of FLI-NAFLD was higher among patients who managed to partially control these factors. Male sex and established organ damage, especially kidney function (1.64; 1.12-2.42), were independent risk predictors. Unlike other diabetes complications, FLI-NAFLD was more frequent among younger patients or those with a shorter duration of diabetes. CONCLUSIONS: FLI-assessed NAFLD is a dynamic condition, with about 5% of diabetic patients entering or leaving the status every year. Younger male patients with insulin resistance or organ damage have a higher risk of presenting with FLI-NAFLD at baseline, developing FLI-NAFLD within 3 years, and a lower probability of regression.

Epidemiology of diabetic kidney disease in adult patients with type 1 diabetes in Italy: The AMD-Annals initiative.

BACKGROUND: Patients with type 1 diabetes mellitus are at increased risk of death. This risk appears to be modulated by kidney dysfunction. The aim of this study was to evaluate the prevalence of diabetic kidney disease (DKD), its traits, and clinical correlates in a large sample of patients with type 1 diabetes. METHODS: Clinical data of 20 464 patients with type 1 diabetes were extracted from electronic medical records. Estimated glomerular filtration rate (eGFR) and increased urinary albumin excretion were considered. RESULTS: Mean age of the patients was 46 ± 16 years, 55.0% were males, and duration of diabetes 19 ± 13 years. The frequency of diabetic kidney disease, low eGFR, and albuminuria was 23.5%, 8.1%, and 19.5%, respectively. In the multivariate analysis the presence of diabetic kidney disease was associated with age (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.10-1.18), duration of diabetes (OR = 1.05, 95% CI: 1.03-1.07), and worse glycemic control (OR = 1.24, 95% CI: 1.21-1.28, for every 1% glycated hemoglobin increase). Diabetic kidney disease was also independently associated with an atherogenic lipid profile and increased systolic blood pressure. Glucose control, systolic blood pressure, triglycerides, and high density lipoprotein cholesterol were associated with both low eGFR and albuminuria. Male gender, retinopathy and smoke were related to albuminuria, being female was related to low eGFR, while SUA levels were associated with DKD, low eGFR and albuminuria. CONCLUSIONS: In our sample of patients with type 1 diabetes, diabetic kidney disease entails an unsafe cardiovascular risk profile. Hyperglycemia, arterial hypertension, and atherogenic lipid profile affected both low eGFR and albuminuria. Retinopathy and smoking were related only to albuminuria while being female and elevated serum uric acid were associated only with low eGFR.

Variability in HbA1c, blood pressure, lipid parameters and serum uric acid, and risk of development of chronic kidney disease in type 2 diabetes.

AIM: Variability in HbA1c and blood pressure is associated with the risk of diabetic kidney disease (DKD). No evidence exists on the role of variability in lipids or serum uric acid (UA), or the interplay between the variability of different parameters, in renal outcomes. METHODS: Within the AMD Annals database, we identified patients with ≥5 measurements of HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), total-, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol, triglycerides, and UA. Patients were followed-up for up to 5 years. The impact of measures of variability on the risk of DKD was investigated by Cox regression analysis and recursive partitioning techniques. RESULTS: Four-thousand, two-hundred and thirty-one patients were evaluated for development of albuminuria, and 7560 for decreased estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2 ). A significantly higher risk of developing albuminuria was associated with variability in HbA1c [upper quartile hazard ratio (HR) = 1.3; 95% confidence interval (CI) 1.1-1.6]. Variability in SBP, DBP, HDL-C, LDL-C and UA predicted the decline in eGFR, the association with UA variability being particularly strong (upper quartile HR = 1.8; 95% CI 1.3-2.4). The concomitance of high variability in HbA1c and HDL-C conferred the highest risk of developing albuminuria (HR = 1.47; 95% CI 1.17-1.84), while a high variability in UA (HR = 1.54; 95% CI 1.19-1.99) or DBP (HR = 1.47; 95% CI 1.11-1.94) conferred the highest risk of decline in eGFR. CONCLUSION: The variability of several parameters influences the development of DKD, having a different impact on albuminuria development and on the decline in GFR.

Achievement of therapeutic targets in patients with diabetes and chronic kidney disease: insights from the Associazione Medici Diabetologi Annals initiative.

BACKGROUND: Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM). METHODS: We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines. RESULTS: In the entire sample, the mean value of HbA1c was 7.2 ± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets. CONCLUSIONS: CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM.

Kidney dysfunction and related cardiovascular risk factors among patients with type 2 diabetes.

BACKGROUND: Kidney dysfunction is a strong predictor of end-stage renal disease and cardiovascular (CV) events. The main goal was to study the clinical correlates of diabetic kidney disease in a large cohort of patients with type 2 diabetes mellitus (T2DM) attending 236 Diabetes Clinics in Italy. METHODS: Clinical data of 120 903 patients were extracted from electronic medical records by means of an ad hoc-developed software. Estimated glomerular filtration rate (GFR) and increased urinary albumin excretion were considered. Factors associated with the presence of albuminuria only, GFR < 60 mL/min/1.73 m(2) only or both conditions were evaluated through multivariate analysis. RESULTS: Mean age of the patients was 66.6 ± 11.0 years, 58.1% were male and mean duration of diabetes was 11.1 ± 9.4 years. The frequency of albuminuria, low GFR and both albuminuria and low GFR was 36.0, 23.5 and 12.2%, respectively. Glycaemic control was related to albuminuria more than to low GFR, while systolic and pulse pressure showed a trend towards higher values in patients with normal kidney function compared with those with both albuminuria and low GFR. Multivariate logistic analysis showed that age and duration of disease influenced both features of kidney dysfunction. Male gender was associated with an increased risk of albuminuria. Higher systolic blood pressure levels were associated with albuminuria, with a 4% increased risk of simultaneously having albuminuria and low GFR for each 5 mmHg increase. CONCLUSIONS: In this large cohort of patients with T2DM, reduced GFR and increased albuminuria showed, at least in part, different clinical correlates. A worse CV risk profile is associated with albuminuria more than with isolated low GFR.

Sexual dysfunction at the onset of type 2 diabetes: the interplay of depression, hormonal and cardiovascular factors.

INTRODUCTION: Several data have emphasized the importance of early diagnosis of erectile dysfunction (ED) and meticulous cardiovascular investigation in the type 2 diabetic mellitus (T2DM) patients. AIM: To estimate the prevalence of ED and its associated determinants in a sample of male patients with new or recently diagnosed T2DM. METHODS: The SUBITO-DE study is an observational, multicenter, prospective study involving 27 Italian diabetes centers. Male patients recently diagnosed with T2DM were consecutively interviewed by their attending physician at the diabetes care centers and asked whether they had experienced a change in their sexual function or found it unsatisfactory. Those responding positively were then invited to participate in the study. MAIN OUTCOME MEASURE: Several hormonal and biochemical parameters were studied. RESULTS: A nonselected series of 1,503 patients was interviewed, 499 of which (mean age, 58.8 ± 8.8 years) entered the study, yielding a final enrolment rate of 33.3%. ED was classified as mild in 19.4%, mild-to-moderate in 15.4%, moderate in 10.4%, and severe in 21.6% of patients, respectively. In addition, premature ejaculation, delayed ejaculation, and hypoactive sexual desire (HSD) were comorbid in 28.3%, 32.9%, and 58.4%, respectively. Finally, hypogonadism, showed an estimated prevalence of almost 20%. Both organic (at least one chronic DM-associated complication) and psychological factors (severe depressive symptoms) increased the risk of ED. Severe depressive symptoms were also associated with ejaculatory problems, HSD, and hypogonadism. CONCLUSIONS: A high prevalence of sexual dysfunction in men with recently diagnosed T2DM was detected. Early diagnosis of ED could help prevent emotional and physical discomfort in men and aid in identifying reversible cardiovascular risk factors. Screening of sexual dysfunction should become a part of routine care in the management of T2DM patients.

Hospitalisation for herpes zoster in people with and without diabetes: A 10-year-observational study.

AIMS: This study explores the association between Herpes Zoster (HZ) hospitalizations and diabetes in Piedmont, Italy from 2010 to 2019. Focusing on the burden of HZ hospitalizations in diabetic and non-diabetic groups, it aims to identify risk factors in diabetics to enhance prevention strategies. METHODS: In a two-phase study, we first compared age-standardized HZ hospitalization rates between diabetic and non-diabetic individuals from 2010 to 2019. We then examined hospitalization risk factors for HZ within a diabetic patient cohort managed by regional diabetes clinics. RESULTS: Of 3,423 HZ hospitalizations in 2010-2019, 17.9 % (613 cases) were diabetic patients, who exhibited higher hospitalization rates (15.9 to 6.0 per 100,000) compared to non-diabetese individuals. Among diabetics subjects risk factors for HZ hospitalization included age over 65, obesity (BMI > 30), and poor glycemic control (HbA1c > 8.0 %). These patients had a 40 % increased rehospitalization risk and a 25 % higher risk of severe complications, such as stroke and myocardial infarction, post-HZ. CONCLUSIONS: Diabetes markedly increases HZ hospitalization rates, rehospitalization, and complication risks. These findings underscore the need for preventive strategies, especially improved glycemic control among high-risk diabetic patients, to inform public health policies and clinical practices aimed at mitigating HZ's impact on this population.

Transparent machine learning suggests a key driver in the decision to start insulin therapy in individuals with type 2 diabetes.

AIMS: The objective of this study is to establish a predictive model using transparent machine learning (ML) to identify any drivers that characterize therapeutic inertia. METHODS: Data in the form of both descriptive and dynamic variables collected from electronic records of 1.5 million patients seen at clinics within the Italian Association of Medical Diabetologists between 2005-2019 were analyzed using logic learning machine (LLM), a "clear box" ML technique. Data were subjected to a first stage of modeling to allow ML to automatically select the most relevant factors related to inertia, and then four further modeling steps individuated key variables that discriminated the presence or absence of inertia. RESULTS: The LLM model revealed a key role for average glycated hemoglobin (HbA1c) threshold values correlated with the presence or absence of insulin therapeutic inertia with an accuracy of 0.79. The model indicated that a patient's dynamic rather than static glycemic profile has a greater effect on therapeutic inertia. Specifically, the difference in HbA1c between two consecutive visits, what we call the HbA1c gap, plays a crucial role. Namely, insulin therapeutic inertia is correlated with an HbA1c gap of <6.6 mmol/mol (0.6%), but not with an HbA1c gap of >11 mmol/mol (1.0%). CONCLUSIONS: The results reveal, for the first time, the interrelationship between a patient's glycemic trend defined by sequential HbA1c measurements and timely or delayed initiation of insulin therapy. The results further demonstrate that LLM can provide insight in support of evidence-based medicine using real world data.

Hepatocellular carcinoma in a large cohort of type 2 diabetes patients.

AIMS: To elucidate the current burden of hepatocellular carcinoma (HCC) in type 2 diabetes (DM2) with a focus on the associated clinical determinants. METHODS: Incidence of HCC between 2009 and 2019 in the diabetic and general population was calculated from regional administrative and hospital databases. Potential determinants of the disease were evaluated with a follow-up study. RESULTS: In the DM2 population, the incidence resulted in 8.05 cases per 10,000 yearly. This rate was three times higher than that of the general population. 137,158 patients with DM2 and 902 HCC were found for the cohort study. The survival of HCC patients was 1/3 of that of cancer-free diabetic controls. Age, male sex, alcohol abuse, previous viral hepatitis B and C, cirrhosis, low platelet count, elevated GGT/ALT, higher BMI and HbA1c levels were associated with HCC occurrence. Diabetes therapy was not adversely associated with HCC development. CONCLUSION: Incidence of HCC in DM2 is more than tripled compared to the general population with high mortality. These figures are higher than those expected from the previous evidence. In parallel with known risk factors for liver disease, such as viruses and alcohol, insulin-resistance characteristics are associated with a higher probability of HCC.

Achieving Good Metabolic Control Without Weight Gain with the Systematic Use of GLP-1-RAs and SGLT-2 Inhibitors in Type 2 Diabetes: A Machine-learning Projection Using Data from Clinical Practice.

PURPOSE: Recently, the 2022 American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) consensus report stressed the importance of weight control in the management of patients with type 2 diabetes; weight control should be a primary target of therapy. This retrospective analysis evaluated, through an artificial-intelligence (AI) projection of data from the AMD Annals database-a huge collection of most Italian diabetology medical records covering 15 years (2005-2019)-the potential effects of the extended use of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and of glucose-like peptide 1 receptor antagonists (GLP-1-RAs) on HbA1c and weight. METHODS: Data from 4,927,548 visits in 558,097 patients were retrospectively extracted using these exclusion criteria: type 1 diabetes, pregnancy, age >75 years, dialysis, and lack of data on HbA1c or weight. The analysis revealed late prescribing of SGLT-2is and GLP-1-RAs (innovative drugs), and considering a time frame of 4 years (2014-2017), a paradoxic greater percentage of combined-goal (HbA1c <7% and weight gain <2%) achievement was found with older drugs than with innovative drugs, demonstrating aspects of therapeutic inertia. Through a machine-learning AI technique, a "what-if" analysis was performed, using query models of two outcomes: (1) achievement of the combined goal at the visit subsequent to a hypothetical initial prescribing of an SGLT-2i or a GLP-1-RA, with and without insulin, selected according to the 2018 ADA-EASD diabetes recommendations; and (2) persistence of the combined goal for 18 months. The precision values of the two models were, respectively, sensitivity, 71.1 % and 69.8%, and specificity, 67% and 76%. FINDINGS: The first query of the AI analysis showed a great improvement in achievement of the combined goal: 38.8% with prescribing in clinical practice versus 66.5% with prescribing in the "what-if" simulation. Addressing persistence at 18 months after the initial achievement of the combined goal, the simulation showed a potential better performance of SGLT-2is and GLP-1-RAs with respect to each antidiabetic pharmacologic class or combination considered. IMPLICATIONS: AI appears potentially useful in the analysis of a great amount of data, such as that derived from the AMD Annals. In the present study, an LLM analysis revealed a great potential improvement in achieving metabolic targets with SGLT-2i and GLP-1-RA utilization. These results underscore the importance of early, timely, and extended use of these new drugs.

The legacy effect of hyperglycemia and early use of SGLT-2 inhibitors: a cohort study with newly-diagnosed people with type 2 diabetes.

Background: A delay in reaching HbA1c targets in patients with newly-diagnosed type 2 diabetes (T2D) is associated with an increased long-term risk of developing cardiovascular diseases (CVD), a phenomenon referred to as legacy effect. Whether an early introduction of glucose-lowering drugs with proven benefit on CVD can attenuate this phenomenon is unknown. Methods: Using data derived from a large Italian clinical registry, i.e. the AMD Annals, we identified 251,339 subjects with newly-diagnosed T2D and without CVD at baseline. Through Cox regressions adjusted for multiple risk factors, we examined the association between having a mean HbA1c between 7.1 and 8% or >8%, compared with ≤7%, for various periods of early exposure (0-1, 0-2, 0-3 years) and the development of later (mean subsequent follow-up 4.6 ± 2.9 years) CVD, evaluated as a composite of myocardial infarction, stroke, coronary or peripheral revascularization, and coronary or peripheral bypass. We performed this analysis in the overall cohort and then splitting the population in two groups of patients: those that introduced sodium-glucose transport protein 2 inhibitors (SGLT-2i) during the exposure phase and those not treated with these drugs. Findings: Considering the whole cohort, subjects with both a mean HbA1c between 7.1 and 8% and >8%, compared with patients attaining a mean HbA1c ≤ 7%, showed an increased risk of developing the outcome in all the three early exposure periods assessed, with the highest risk observed in patients with mean HbA1c > 8% in the 3 years exposure period (hazard ratio [HR]1.33; 95% confidence interval [CI] 1.063-1.365). The introduction of SGLT-2i during the exposure periods of 0-1 and 0-2 years eliminated the association between poor glycemic control and the outcome (p for interaction 0.006 and 0.003, respectively, vs. patients with the same degree of glycemic control but not treated with these drugs). Interpretation: Among patients with newly diagnosed T2D and free of CVD at baseline, a poor glycemic control in the first three years after diagnosis is associated with an increased subsequent risk of CVD. This association is no longer evident when SGLT-2i are introduced in the first two years, suggesting that these drugs attenuate the phenomenon of legacy effect. An early treatment with these drugs might thus promote a long-lasting benefit in patients not attaining proper glycemic control after T2D diagnosis. Funding: This work was supported, in part, by the Italian Ministry of Health (Ricerca Corrente) to IRCCS MultiMedica.