Search

Aims: To compare medication persistence and efficacy of oral and subcutaneous semaglutide, in a real-world setting., Materials and Methods: This is a single-center, retrospective observational cohort study. Patients with type 2 diabetes mellitus (T2DM) starting treatment with either formulation of semaglutide between January 1 2019 and July 31 2023 and with at least one follow-up visit were included. The primary endpoint was the difference in the proportion of patients that continued treatment after 6, 12 and 18 months. Main secondary endpoints were change in HbA1c and body weight., Results: We included 242 patients on oral (n = 121) and subcutaneous (n = 121) semaglutide. At baseline, patients in the oral semaglutide group were significantly older (mean age: 67 ± 11 vs. 63 ± 11 years, p = 0.002) and had a lower body mass index (BMI: 30.5 ± 5.6 vs. 33.9 ± 7.1 kg/m 2 , p < 0.001). The proportion of patients persistent to treatment was significantly lower in the oral group at 6 (85.3% vs. 94.8%; p < 0.001), 12 (72.3% vs. 92.4%, p < 0.001) and 18 (46.0% vs. 83.8%; p < 0.001) months. Most common reasons for discontinuation were gastro-intestinal side effects. When adjusted for age and BMI, body weight and HbA1c reduction were not significantly different between the two formulations, as the proportion of patients achieving the composite outcome of weight loss ≥ 5% and HbA1c < 7.0%., Conclusions: The present real-world study suggests that persistence is significantly lower when semaglutide is administered as a once-daily tablet compared with a weekly injection, while there are no differences in efficacy between the two formulations., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to report., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Competing Interests: We declare no competing interests.

Natriuretic peptides (NPs) are polypeptide hormones involved in the homeostasis of the cardiovascular system. They are produced by cardiomyocytes and regulate circulating blood volume and sodium concentration. Clinically, measurements of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are recommended by international guidelines as evidence is accumulating on their usefulness. They have a high negative predictive value, and in the setting of low NPs, a diagnosis of heart failure (HF) can be safely excluded in both emergency (BNP < 100 pg/mL, NT-proBNP < 300 pg/mL) and outpatient settings (BNP < 35 pg/mL and NT-proBNP < 125 pg/mL). Moreover, the 2023 consensus from the European Society of Cardiology suggests threshold values for inclusion diagnosis. These values are also associated with increased risks of major cardiovascular events, cardiovascular mortality, and all-cause mortality whether measured in inpatient or outpatient settings. Among patients without known HF, but at high risk of developing it (e.g., in the setting of diabetes mellitus, hypertension, or atherosclerotic cardiovascular disease), NPs may be useful in stratifying cardiovascular risk, optimizing therapy, and reducing the risk of developing overt HF. In the diabetes setting, risk stratification with the use of these peptides can guide the physician to a more informed and appropriate therapeutic choice as recommended by guidelines. Notably, NP levels should be carefully interpreted in light of certain conditions that may affect their reliability, such as chronic kidney disease and obesity, as well as demographic variables, including age and sex. In conclusion, NPs are useful in the diagnosis and prognosis of HF, but they also offer advantages in the primary prevention setting.

Context: Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk has changed in recent years., Objective: The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population., Methods: Data were retrieved from the health care utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost 10 million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related, and nonviral nonalcohol related (NVNA)., Results: Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The standardized mortality ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis, and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer., Conclusion: While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes made up the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: Clinical trials have shown that in type 2 diabetes mellitus (T2D) resting office heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk, a worse prognosis and an unfavorable outcome. The present study was aimed at investigating whether the above mentioned treshold HR values reflect a sympathetic overdrive of marked degree., Methods: In 58 T2D patients (age range: 39-57 years) without signs of autonomic neuropathy and in 52 age-matched healthy controls, we assessed muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC), subdividing the study population in different subgroups according to their clinic and 24-h HR values., Results: In T2D progressively greater clinic and 24-h HR values were accompanied by progressive increases in MSNA and NE. HR cutoff values indicated by clinical trials as associated with an increased cardiovascular risk (> 70 beats/minute) were accompanied by MSNA values significantly higher than those detected in patients with lower HR, this being the case also for NE. In T2D both MSNA and NE were significantly related to clinic (r = 0.93, P < 0.0001 and r = 0.87, P < 0.0001, respectively) and 24-h (r = 0.92, P < 0.0001 and r = 0.84, P < 0.0001, respectively) HR. The MSNA and NE behaviour observed in T2D was not detected in healthy controls., Conclusions: In T2D clinic HR values allow to detect patients with a greater sympathetic overactivity. Considering the adverse clinical impact of the sympathetic overdrive on prognosis, our data emphasize the need of future studies investigating the potential usefulness of lifestyle and pharmacological interventions exerting sympathomodulatory effects., (© 2024. The Author(s).)

A recent Delphi consensus proposed a new definition for metabolic dysfunction associated steatotic liver disease (MASLD) and introduced a disease entity called MetALD, a condition in which steatotic liver disease (SLD), metabolic dysfunction and moderate alcohol intake coexist. Given the limited available data on the prognostic implications of these disease entities, we performed a systematic review and meta-analysis of available cohort studies to evaluate the association of MASLD and MetALD with hard clinical outcomes. We included 5 studies for a total of 9 824 047 participants. Compared with participants without SLD, increased rates of all-cause mortality and incident cardiovascular disease were present for both MASLD and MetALD. Moreover, MetALD was also associated with significantly higher risks of cancer-related mortality (n = 2 studies, random-effects HR 2.10, 95% CI 1.35-3.28) and cardiovascular mortality (n = 3 studies, random-effects HR 1.17, 95% CI 1.12-1.22). Although preliminary, available evidence indicates a more unfavourable prognosis for patients with MetALD compared with those with MASLD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM)., Materials and Methods: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007-2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system., Results: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72-0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55-0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA., Conclusions: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Objective: The purpose of this study was to determine the effectiveness of a new AI-based tool called NAIF (NAFLD-AI-Fibrosis) in identifying individuals from the general population with advanced liver fibrosis (stage F3/F4). We compared NAIF's performance to two existing risk score calculators, aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (Fib4)., Methods: To set up the algorithm for diagnosing severe liver fibrosis (defined as Fibroscan® values E ≥ 9.7 KPa), we used 19 blood biochemistry parameters and two demographic parameters in a group of 5,962 individuals from the NHANES population (2017-2020 pre-pandemic, public database). We then assessed the algorithm's performance by comparing its accuracy, precision, sensitivity, specificity, and F1 score values to those of APRI and Fib4 scoring systems., Results: In a kept-out sub dataset of the NHANES population, NAIF achieved a predictive precision of 72 %, a sensitivity of 61 %, and a specificity of 77 % in correctly identifying adults (aged 18-79 years) with severe liver fibrosis. Additionally, NAIF performed well when tested with two external datasets of Italian patients with a Fibroscan® score E ≥ 9.7 kPa, and with an external dataset of patients with diagnosis of severe liver fibrosis through biopsy., Conclusions: The results of our study suggest that NAIF, using routinely available parameters, outperforms in sensitivity existing scoring methods (Fib4 and APRI) in diagnosing severe liver fibrosis, even when tested with external validation datasets. NAIF uses routinely available parameters, making it a promising tool for identifying individuals with advanced liver fibrosis from the general population. Word count abstract: 236., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Context: Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies., Objective: To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality., Methods: One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015., Results: The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality., Conclusion: We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognostication., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aim: Liver fibrosis is the strongest predictor of liver-related mortality in many chronic liver diseases. NT-ProBNP is independently associated with cardiovascular mortality in general population settings. Here, we evaluate the relative contribution of non-invasively identified liver fibrosis and NT-ProBNP on all-cause and cardiovascular mortality in patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD)., Methods and Results: Serum NT-ProBNP levels were measured in 4229 patients with MASLD from the general population without a known history of heart failure that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. Presence of liver fibrosis was estimated using the Fibrosis-4 index (FIB-4). We applied Cox proportional hazard models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP and FIB-4 levels and all-cause and cardiovascular mortality through December 2019. Mortality was lower for participants with normal levels of both biomarkers, intermediate if a single biomarker was elevated and highest when both were above the chosen threshold. In the multivariable-adjusted models, both elevated FIB-4 (≥2.67) and elevated NT-ProBNP levels (≥125 pg/ml) were independently associated with higher risks of all-cause mortality (HR 2.2, 95 % CI 1.5-3.2 and HR 1.6, 95 % CI 1.4-2.0, respectively) and cardiovascular mortality (HR 2.1, 95 % CI 1.2-3.7 and HR 2.1, 95 % CI 1.5-2.9, respectively). The associations remained consistent in subgroup analyses based on sex, obesity and age., Conclusions: Both FIB-4 and NT-ProBNP are independently associated with higher mortality in patients with MASLD. Their combined use might prove useful to risk-stratify patients in clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering agents widely used for the treatment of type 2 diabetes mellitus. A number of clinical trials in type 2 diabetic patients with different degrees of renal impairment have clearly demonstrated that SGLT2 inhibitors reduce the progression rate of diabetic kidney disease. Furthermore, recent studies have shown that SGLT2 inhibitors also exert a protective effect in the case of non-diabetic kidney disease. Consequently, it has been hypothesized that the nephroprotective activity of these drugs could exceed the canonical impact on glycemic control and that the resulting beneficial effects could be the consequence of their pleiotropic properties (proven reduction of inflammation, fibrosis, oxidative stress and sympathetic nervous activity) both at systemic and tissue levels, suggesting that the efficacy of these drugs could also be extended to non-diabetic nephropathies. This review focuses on the nephroprotective effects of SGLT2 inhibitors in different experimental models of non-diabetic kidney disease. The different glucose-independent mechanisms potentially implemented by SGLT2 inhibitors to ultimately protect the non-diabetic kidney are described in detail, and conflicting results, when present, are discussed.

Background and Aims: Several studies reported an association between liver stiffness measurement (LSM) obtained through vibration-controlled transient elastography (VCTE) and all-cause mortality in patients with nonalcoholic fatty liver disease (NAFLD). The objective of this systematic review and meta-analysis was to summarize available evidence on the nature and magnitude of this association., Methods: We systematically searched PubMed-MEDLINE and Scopus up to April 2023 for observational cohort studies in which LSM was measured with VCTE in patients with NAFLD or in general population settings, with a follow-up ≥1 year and with available data on all-cause mortality. Measures of association from individual studies were meta-analysed using random effects models. Of the 517 titles initially scrutinized, we included seven studies with data on 18 771 participants (47.1% male) and a mean follow-up of 3.6 years. We included effect estimates obtained in the models with the highest degree of adjustment for potential confounders available in each study., Results: When analysed as a categorical variable based on specific LSM cut-offs, liver fibrosis was associated with an increased risk of all-cause death (HR 2.10, 95% CI 1.56-2.83; test for overall effect z = 4.919, p < 0.001). Results were consistent when LSM was considered as a continuous variable (HR for 1 kPa increase: 1.03, 95% CI 1.01-1.05; test for overall effect z = 3.341, p = 0.001). There was borderline significant heterogeneity among the studies (I 2  = 50.2% and I 2  = 66.7% in the two analyses, respectively). No significant publication bias was detected by funnel plot analysis and Egger's and Begg's tests., Conclusion: The present meta-analysis indicates that LSM, as a proxy of liver fibrosis, is independently and directly associated with a higher mortality risk in patients with NAFLD., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Objective: The aim of the present study is to explore the epidemiologic impact of the definition of steatotic liver disease (SLD) proposed by a multi-society (American Association for the Study of the Liver-the European Association for the Study of Liver Diseases-Asociación Latinoamericana para el Estudio del Hígado) Delphi consensus statement., Methods: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey who were evaluated by vibration-controlled transient elastography. Hepatic steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter and liver stiffness measurement using cut-offs of 274 dB/m and 8.0 kPa, respectively. Recently proposed criteria for metabolic dysfunction-associated steatotic liver disease (MASLD), MetALD (MASLD + significant alcohol consumption), MASLD-Viral hepatitis and cryptogenic SLD were applied., Results: SLD was present in 42.1% (95% CI: 40.3-43.9) of the 3173 included participants. Among patients with SLD, 99.4% met the metabolic dysfunction definition. Moreover, 89.4%, 7.7%, 2.4%, 0.4% and 0.1% were defined as MASLD, MetALD, MASLD-Viral, alcoholic liver disease (ALD) (significant alcohol consumption without metabolic dysfunction) and cryptogenic, respectively. No patients without metabolic dysfunction had significant liver fibrosis, which was present in 15.2%, 9.5% and 19.5% of patients with MASLD, MetALD and MASLD-viral, respectively. Approximately, 90% of the overall adult US population could be diagnosed with metabolic dysfunction according to the consensus criteria. A high degree of concordance was found between MASLD and the previously proposed metabolic dysfunction-associated fatty liver disease definition., Conclusions: Metabolic dysfunction is present in almost all patients with SLD in the United States. The new change in diagnostic criteria did not significantly impact disease prevalence., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD) affects ~70% of patients with type 2 diabetes (T2D), with ~20% showing signs of advanced liver fibrosis. Patients with T2D are at an increased risk of developing cirrhosis, liver failure, and hepatocellular carcinoma and their liver-related mortality is doubled compared with non-diabetic individuals. Nonetheless, the condition is frequently overlooked and disease awareness is limited both among patients and among physicians. Given recent epidemiological evidence, clinical practice guidelines recommend screening for NAFLD/MASLD and advanced liver fibrosis in patients with T2D. While many drugs are currently being tested for the treatment of NAFLD/MASLD, none of them have yet received formal approval from regulatory agencies. However, several classes of antidiabetic drugs (namely pioglitazone, sodium-glucose transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and multi-agonists) have shown favorable effects in terms of liver enzymes, liver fat content and, in some occasions, on histologic features such as inflammation and fibrosis. Therefore, diabetologists have the opportunity to actively treat NAFLD/MASLD, with a concrete possibility of changing the natural history of the disease. In the present narrative review, we summarize evidence and clinical recommendations for NAFLD/MAFLD screening in the setting of T2D, as well as on the effect of currently available glucose-lowering drugs on hepatic endpoints.

Introduction: Serum neurofilament light chain (sNfL) levels are biomarkers of neuro-axonal injury in multiple neurological diseases. Little is known on their potential role as prognostic markers in people without known neurological conditions., Objective: The aim of this study is to evaluate the association between sNfL levels and all-cause mortality in a general population setting., Methods: sNfL levels were measured in 2071 people aged 25-75 years from the general US population that participated in the 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES). Cognitive function was evaluated in a subset of participants aged 60-75 years using the Consortium to Establish a Registry for Alzheimer's Disease-Word Learning test, the Animal Fluency test and the Digit Symbol Substitution test. We applied Cox proportional hazard models adjusted for several potential confounders to evaluate the association between sNfL and all-cause mortality through December 2019 by linking NHANES data with data from the National Death Index., Results: In a cross-sectional analysis, higher sNfL levels were associated with worse performance in all three cognitive function tests. Over a median follow-up of 6.1 years, 85 participants died. In a multivariable model adjusted for age, sex, race-ethnicity, diabetes, chronic kidney disease, harmful alcohol consumption, cigarette smoke and prevalent cardiovascular disease, higher sNfL levels were significantly and positively associated with all-cause mortality (HR per unit increase in log-transformed sNfL: 2.46, 95% CI 1.77-3.43, p < 0.001). Results were robust when analyses were stratified according to age, sex, body mass index and kidney function., Conclusion: We found a positive association between sNfL levels and mortality in the general US population. Further studies are needed to understand the biological mechanisms underlying this association., (© 2023. The Author(s).)

Sex hormones impact body composition. Data on the specific impact of each hormone on different body depots in men and women are scarce. The aim of this study is to evaluate the association between testosterone, estradiol and body fat distribution in the general population. This is a population-based cross-sectional study based on data from the 2013-2016 cycles of the National Health and Nutrition Examination Survey. Dual energy X-ray absorptiometry (DXA) and liquid chromatography tandem mass spectrometry were performed on participants aged 18-59 years to evaluate body composition and sex hormone levels, respectively. Weighted multivariable linear regression analyses were performed to evaluate the association between these parameters after adjustment for potential confounders. A total of 6655 participants (3309 males and 3346 females) was included in the analysis. Men with lower testosterone levels were older, had a higher body mass index (BMI) and had a generally unfavorable metabolic profile, while no specific trends were found in women. Among men, testosterone was positively associated with lean body mass and was negatively associated with fat mass and the android/gynoid (A/G) ratio, while an opposite trend was found for estradiol. Among women, testosterone did not impact body composition, while estradiol levels were positively associated with lean mass and were negatively associated with fat mass. Our results support the notion that the impact of different sex hormones on specific fat depots varies substantially between men and women.

Aims: Evidence on the role of 25-Hydroxyvitamin D (25(OH)D) in the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) is conflicting and population-based data are scarce. Here, we assess the association between 25(OH)D levels, NAFLD and liver fibrosis in the general population., Materials and Methods: This is an analysis of data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey. We included adult participants with available data on vibration-controlled transient elastography (VCTE) and without viral hepatitis and significant alcohol consumption. Steatosis and fibrosis were diagnosed by the median values of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. 25(OH)D was measured by high performance liquid chromatography-tandem mass spectrometry., Results: A total of 3970 participants (1928 men and 2042 women) were included in the study. The prevalence of NAFLD (CAP ≥ 274 dB/m) and significant liver fibrosis (LSM ≥ 8 kPa) were 41.7% (95% CI 39.4-44.0) and 8.4% (95% CI 7.0-9.9), respectively, while 21.1% (95% CI 17.3-25.4) of participants had low 25(OH)D levels (<50 nmol/L). A multivariable logistic regression model adjusted for age, sex, race-ethnicity, body mass index, waist circumference, calendar period, diabetes, chronic kidney disease, and vitamin D supplementation showed that compared with participants with low 25(OH)D, those with optimal levels (≥75 nmol/L) had lower odds of both NAFLD (OR 0.73, 95% CI 0.55-0.98 p = 0.038) and significant liver fibrosis (OR 0.65, 95% CI 0.44-0.96, p = 0.033)., Conclusions: An inverse relationship was found between 25(OH)D and NAFLD and fibrosis, suggesting a possible role of vitamin D in NAFLD occurrence and progression., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

Aim: Identifying patients with fibrotic nonalcoholic steatohepatitis (NASH) is crucial in order to refer them to specialist care as fibrotic NASH represents one of the major inclusion criteria for clinical trials. The aim of this study is to report the prevalence of fibrotic NASH in the general US population across the spectrum of glucose tolerance and evaluate the performance of the recently proposed Fibrotic NASH Index (FNI)., Methods: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey. Participants with available data to calculate FNI (which is based on AST, HbA1c and HDL-cholesterol) and with a reliable vibration controlled transient elastography examination were included. We excluded participants with chronic viral hepatitis, significant alcohol consumption or other forms of liver disease. Probable fibrotic NASH was defined as a Fibroscan-AST (FAST) score ≥ 0.35., Results: We included a total of 6268 participants. The overall prevalence of probable fibrotic NASH was 5.9 % (95 % CI 5.2-6.7) and it increased progressively from participants with normal glucose tolerance (3.7 %, 95 % CI 2-9-4.7) to those with diabetes (14.7 %, 95 % CI 12.1-17.8). The performance of FNI for probable fibrotic NASH was satisfactory in the overall population (area under the receiver operating characteristic curve (AUROC): 0.93, 95 % CI 0.92-0.94) and it maintained a good accuracy also in participants with diabetes (n = 1113, AUROC 0.89, 95 % CI 0.86-0.92). In all groups it outperformed Fibrosis-4., Conclusions: FNI is an easy and reliable test to screen for NASH and its performance is maintained in patients with diabetes, a condition that was shown to negatively influence the performance of several non-invasive scores., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: To evaluate the protective effect of oral antidiabetic drugs in a large cohort of elderly patients with type 2 diabetes differing for age, clinical status, and life expectancy, including patients with multiple comorbidities and short survival., Methods: A nested case-control study was carried out by including the cohort of 188,983 patients from Lombardy (Italy), aged ≥ 65 years, who received ≥ 3 consecutive prescriptions of antidiabetic agents (mostly metformin and other older conventional agents) during 2012. Cases were the 49,201 patients who died for any cause during follow-up (up to 2018). A control was randomly selected for each case. Adherence to drug therapy was measured by considering the proportion of days of the follow-up covered by the drug prescriptions. Conditional logistic regression was used to model the risk of outcome associated with adherence to antidiabetic drugs. The analysis was stratified according to four categories of the clinical status (good, intermediate, poor, and very poor) differing for life expectancy., Results: There was a steep increase in comorbidities and a marked reduction of the 6-year survival from the very good to the very poor (or frail) clinical category. Progressive increase in adherence to treatment was associated with a progressive decrease in the risk of all-cause mortality in all clinical categories and at all ages (65-74, 75-84 and ≥ 85 years) except for the frail patient subgroup aged ≥ 85 years. The mortality reduction from lowest to highest adherence level showed a tendency to be lower in frail patients compared to the other categories. Similar although less consistent results were obtained for cardiovascular mortality., Conclusions: In elderly diabetic patients, increased adherence to antidiabetic drugs is associated with a reduction in the risk of mortality regardless of the patients' clinical status and age, with the exception of very old patients (age ≥ 85 years) in the very poor or frail clinical category. However, in the frail patient category the benefit of treatment appears to be less than in patients in good clinical conditions., (© 2023. The Author(s).)

Data are limited on the epidemiology of fibrotic non-alcoholic steatohepatitis (NASH). We applied the recently proposed Fibrotic NASH Index (FNI) to estimate trends in the prevalence of probable fibrotic NASH in the general United States population using data from the 1999-2016 cycles of the National Health and Nutrition Examination Survey. A total of 40 273 participants aged 20 years and older were included in the analysis. The prevalence of probable fibrotic NASH (FNI ≥0.33) in the overall population was 8.4% (95% CI 8.0-8.8), with higher values found in males and in Hispanic participants. It increased from 6.9% (95% CI 6.3-7.6) in 1999-2004 to 9.2% (95% CI 8.4-10.0) in 2011-2016. This positive trend was evident in both sexes and in participants with obesity and diabetes. Finally, it increased progressively with increasing age, body mass index and worse glucose tolerance. NASH prevalence is increasing in the general US population, synchronous with increasing rates of obesity and type 2 diabetes., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The progress of digital transformation in clinical practice opens the door to transforming the current clinical line for liver disease diagnosis from a late-stage diagnosis approach to an early-stage based one. Early diagnosis of liver fibrosis can prevent the progression of the disease and decrease liver-related morbidity and mortality. We developed here a machine learning (ML) algorithm containing standard parameters that can identify liver fibrosis in the general US population., Materials and Methods: Starting from a public database (National Health and Nutrition Examination Survey, NHANES), representative of the American population with 7265 eligible subjects (control population n = 6828, with Fibroscan values E < 9.7 KPa; target population n = 437 with Fibroscan values E ≥ 9.7 KPa), we set up an SVM algorithm able to discriminate for individuals with liver fibrosis among the general US population. The algorithm set up involved the removal of missing data and a sampling optimization step to managing the data imbalance (only ∼ 5 % of the dataset is the target population)., Results: For the feature selection, we performed an unbiased analysis, starting from 33 clinical, anthropometric, and biochemical parameters regardless of their previous application as biomarkers of liver diseases. Through PCA analysis, we identified the 26 more significant features and then used them to set up a sampling method on an SVM algorithm. The best sampling technique to manage the data imbalance was found to be oversampling through the SMOTE-NC. For final model validation, we utilized a subset of 300 individuals (150 with liver fibrosis and 150 controls), subtracted from the main dataset prior to sampling. Performances were evaluated on multiple independent runs., Conclusions: We provide proof of concept of an ML clinical decision support tool for liver fibrosis diagnosis in the general US population. Though the presented ML model represents at this stage only a prototype, in the future, it might be implemented and potentially applied to program broad screenings for liver fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Context: Serum neurofilament light chain (sNfL) levels are biomarkers of neuroaxonal injury in multiple neurological diseases., Objective: Given the paucity of data on the distribution of sNfL levels in the general population, in the present study we identified predictors of sNfL levels in a community setting and investigated the association between diabetes and sNfL., Methods: sNfL levels were measured in 2070 people aged 20 to 75 years from the general US population (275 with and 1795 without diabetes) that participated in the 2013-2014 cycle of the National Health and Nutrition Examination Survey. We evaluated the association between diabetes and sNfL levels after adjustment for age, sex, race-ethnicity, alcohol use, and kidney function using a multivariable linear regression model. Cognitive function was evaluated in a subset of participants aged 60 to 75 years using the Consortium to Establish a Registry for Alzheimer's Disease-Word Learning test, the Animal Fluency test, and the Digit Symbol Substitution test., Results: The weighted prevalence of diabetes was 10.4% (95% CI, 9.0-11.9). In each age stratum, patients with diabetes exhibited higher sNfL levels compared with nondiabetic participants. Age, proportion of males, prevalence of diabetes, and homeostatic model of insulin resistance increased progressively across quartiles of sNfL levels in the overall population, whereas estimated glomerular filtration rate (eGFR) showed an opposite trend. In the multivariable model, age, sex, eGFR, alcohol use and diabetes were significantly associated with sNfL levels. Moreover, higher sNfL levels were associated with worse performance in all 3 cognitive function tests., Conclusion: Diabetes is associated with higher sNfL. Further large-scale and prospective studies are needed to replicate our results and evaluate the ability of sNfL to predict the incidence of neuropathy and dementia in this patient population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiovascular risk and body-weight management are both emerging challenges of type 1 diabetes care. We evaluated the association between intraindividual variability of body-weight and risk of cardiovascular events in people with type 1 diabetes., Methods: We analyzed 1,398 participants from the DCCT/EDIC studies. Five indices of intraindividual variability of body-weight were calculated for each participant taking into account body-weight measures obtained during the DCCT follow-up (average 6 ± 2 years). The Average Successive Variability (ASV) index, the main variable of interest, was defined as the average absolute difference between successive body-weight measures. The primary outcome was a composite of major adverse cardiovascular events (MACE: nonfatal myocardial infarction or stroke, or cardiovascular death) occurring during the subsequent EDIC follow-up (20 ± 3 years). All-cause death was a secondary outcome. Risk of outcomes were assessed by Cox proportional hazards regression analyses, adjusted for traditional cardiovascular risks factors, including BMI., Results: The cumulative incidence of MACE and all-cause death during follow-up were 5.6% (n = 79) and 6.8% (n = 95), respectively. The adjusted Hazard Ratio (HR) for MACE by every increase of 1 standard deviation (SD) of ASV was 1.34 (95% CI, 1.06-1.66), p = 0.01. For all-cause death, the adjusted HR for 1 SD increase of ASV was 1.25 (1.03-1.50), p = 0.03. Similar results were observed when considering the other indices of intraindividual variability of body-weight., Conclusions: High body-weight variability (body-weight cycling) is associated with increased risk of MACE and all-cause death in people with type 1 diabetes, independently of the BMI and traditional cardiovascular risk factors., (© 2022. The Author(s).)

Background: Even though hyperglycemia is a well-known cardiovascular risk factor, the absolute risk of cardiovascular events varies to a great extent within each glycemic category. The aim of this study is to evaluate whether N-terminal pro-B natriuretic peptide (NT-ProBNP) could help identify subjects at higher cardiovascular risk, independently of blood glucose levels., Methods: Serum NT-ProBNP levels were measured in 5502 people aged 45-79 years without heart failure from the general population (3380 with normoglycemia, 1125 with pre-diabetes and 997 with diabetes) that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. We applied Cox and Fine Gray models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP levels and all-cause and cardiovascular mortality through December 2015., Results: After a median follow-up of 13 years, 1509 participants died, 330 of cardiovascular causes. In the multivariable-adjusted models, compared with participants with NT-ProBNP &lt; 100 pg/ml, those with levels 100-300 pg/ml and ≥ 300 pg/ml had a higher incidence of both all-cause mortality (HR 1.61, 95% CI 1.12-2.32, p = 0.012 and HR 2.96, 95% CI 1.75-5.00, p &lt; 0.001, respectively) and cardiovascular mortality (HR 1.57, 95% CI 1.17-2.10, p = 0.011 and HR 2.08, 95% CI 1.47-2.93, p &lt; 0.001, respectively). The association was consistent in subgroup analyses based on glycemic status, obesity, age and sex., Conclusions: Elevated NT-ProBNP is independently associated with all-cause and cardiovascular mortality in the general population and could help identify patients at the highest risk. Further studies are needed to evaluate whether intensification of treatment based on biomarker data might lead to improvements in cardiovascular risk reduction., (© 2022. The Author(s).)

Background and Aims: Glycated albumin (GA) reflects short-term glycemic control, but few data are available on its association with hard clinical outcomes. The purpose of this study is to evaluate the association between GA levels and all-cause and cardiovascular mortality in people with and without a previous diagnosis of diabetes., Methods and Results: Serum GA levels were measured in 12147 people from the general population (1319 with and 10828 without diabetes) that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey (NHANES). We evaluated the association between GA and all-cause and cardiovascular mortality through December 2015 by linking NHANES data with data from the National Death Index. Associations were compared with those observed for hemoglobin A1c (HbA1c). After a median follow-up of 13 years, 2785 participants (619 with and 2166 without diabetes) died, 651 of cardiovascular causes. Multivariable-adjusted Cox proportional hazard models showed that higher baseline GA levels were significantly associated with a higher incidence of both outcomes in participants with (all-cause: HR 1.03, 95% CI 1.01-1.04; cardiovascular: HR 1.04, 95% CI 1.02-1.07) and without diabetes (all-cause: HR 1.05, 95% CI 1.03-1.08; cardiovascular: HR: 1.08, 95% CI 1.02-1.14); on the other hand, we found a trend for increased mortality with increasing HbA1c levels in patients with known diabetes, but not in participants without., Conclusions: For a novel measure of hyperglycemia to be considered useful, its association with hard, long term clinical outcomes is of great importance. We showed that GA is associated with mortality in the general population independently of a previous diagnosis of diabetes., Competing Interests: Conflict of interest All authors declare no conflicts of interest related to this study., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study is to evaluate trends in heart failure (HF) prevalence, impact of accompanying risk factors and use of effective therapeutic regimens during the last two decades in the general adult US population., Methods: We analyzed data obtained from the 1999-2018 cycles of the National Health and Nutrition Examination Survey (NHANES). Among a total of 34,403 participants 40 years or older who attended the mobile examination center visit, 1690 reported a diagnosis of HF. Trends in participant features across calendar periods were assessed by linear regression for continuous variables and logistic regression for binary variables., Results: Prevalence of self-reported HF did not change significantly from 1999 to 2002 to 2015-2018 (~3.5%), while obesity and diabetes showed a progressive increase in prevalence, affecting ~65% and ~ 45% of patients with HF in the most recent calendar period, respectively. In parallel, use of glucose lowering drugs (especially metformin and insulin) as well as statins increased from 1999 to 2010, with significant improvement of the lipid control. A modest improvement in blood pressure control was achieved in association with a significant increase in the use of angiotensin receptor blockers and beta-blockers., Conclusions: In the last 20 years, the prevalence of HF in US adults remained stable, while both obesity and diabetes increased, with the two conditions affecting half of patients with HF. Improvements in the control of dyslipidemia and, to a lesser extent, blood pressure, was detected; nonetheless, a significant gap remains in guideline-directed use of HF and diabetes medications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background & Aims: Liver stiffness is an indirect marker of liver fibrosis, which predicts clinical outcomes in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present systematic review and meta-analysis is to summarize evidence on the prevalence of elevated liver stiffness in patients with diabetes., Methods: We systematically searched PubMed-MEDLINE and Scopus from inception to May 2022 for observational studies reporting the prevalence of elevated liver stiffness diagnosed by vibration controlled transient elastography (VCTE) in adult patients with either type 1 (T1D) or type 2 diabetes (T2D). Prevalence values from individual studies were meta-analyzed using random effects models. Subgroup and sensitivity analyses were performed to identify potential sources of heterogeneity., Results: Of the 428 titles initially scrutinized, 29 studies fulfilled the criteria and were included, providing data on 390 patients with T1D and 10,487 patients with T2D. Prevalence rates of elevated liver stiffness were 5.2% (95% CI 1.1-9.2) in patients with T1D and 19.8% (95% CI 16.8-22.8) in patients with T2D. In studies performed in patients with T2D, multivariate meta-regression analysis showed that higher body mass index, higher age, a higher proportion of males, lower VCTE cut-off and Asian ethnicity were associated with increased prevalence rates. This model explained 32.7% of the observed heterogeneity. No signs of publication bias were identified by visual inspection of the funnel plot or by Egger's test., Conclusions: This meta-analysis indicates that 1 in 20 patients with T1D and 1 in 5 patients with T2D has elevated liver stiffness, indicative of potential significant or advanced liver fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Recently, an expert panel proposed diagnostic criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) in the pediatric population. The aim of this study was to evaluate the prevalence of MAFLD among US adolescents and to investigate whether the new MAFLD definition is able to identify individuals with more advanced liver disease. We analyzed data from participants 12-18 years old included in the 2017-2020 cycles of the National Health and Nutrition Examination Survey, a large survey aimed at including individuals representative of the non-institutionalized general US population. Participants with a complete vibration-controlled transient elastography exam were included. Steatosis was evaluated through the median controlled attenuation parameter (CAP) and fibrosis through median liver stiffness measurement (LSM). Recently proposed criteria for the diagnosis of MAFLD were applied. Multivariable logistic regression analysis was performed to evaluate the impact of the new MAFLD definition on the odds of significant liver fibrosis. We included a total of 1446 adolescents (mean age: 14.9 years; 52.0% male; 47.3% overweight or obese). No participant reported a previous history of viral hepatitis. Steatosis (CAP ≥ 248 dB/m) was present in 25.9% (95% confidence interval [CI] 23.3-28.9) of individuals, and among these, 87.7% met the MAFLD criteria. Only 22.9% of patients with steatosis had elevated alanine aminotransferase levels. Among participants with steatosis, prevalence of significant liver fibrosis (LSM ≥ 7.4 kPa) did not differ significantly according to whether they met MAFLD criteria (9.7% vs. 15.2%, p = 0.276). In the multivariable model, odds of significant fibrosis did not differ significantly between these two groups. MAFLD criteria are met by most US adolescents with elastographic evidence of steatosis. Nonetheless, these criteria do not appear to improve detection of subjects with more advanced liver disease. Further longitudinal studies are needed to evaluate whether metabolic dysfunction is associated with faster progression toward inflammation, fibrosis, and liver-related events., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Context: It is still debated whether prolonged use of proton pump inhibitors (PPIs) might affect metabolic health., Objective: To investigate the relationship between prolonged use of PPIs and the risk of developing diabetes., Methods: We performed a case-control study nested into a cohort of 777 420 patients newly treated with PPIs between 2010 and 2015 in Lombardy, Italy. A total of 50 535 people diagnosed with diabetes until 2020 were matched with an equal number of controls that were randomly selected from the cohort members according to age, sex, and clinical status. Exposure to treatment with PPIs was assessed in case-control pairs based on time of therapy. A conditional logistic regression model was fitted to estimate the odds ratios and 95% CIs for the exposure-outcome association, after adjusting for several covariates. Sensitivity analyses were performed to evaluate the robustness of our findings., Results: Compared with patients who used PPIs for < 8 weeks, higher odds of diabetes of 19% (95% CI, 15-24), 43% (38-49), and 56% (49-64) were observed among those who used PPIs for between 8 weeks and 6 months, 6 months and 2 years, and > 2 years, respectively. The results were consistent when analyses were stratified according to age, sex, and clinical profile, with higher odds ratios being found in younger patients and those with worse clinical complexity. Sensitivity analyses revealed that the association was consistent and robust., Conclusions: Regular and prolonged use of PPIs is associated with a higher risk of diabetes. Physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Few population-based studies have investigated the association between body fat distribution and the risk of nonalcoholic fatty liver disease (NAFLD) and significant liver fibrosis., Objectives: We aimed to evaluate the relations of total body fat and body fat distribution with NAFLD in the general US population., Methods: This is a cross-sectional, population-based study based on the 2017-2018 cycle of the NHANES. Participants aged 18-59 y without known liver conditions or significant alcohol consumption were studied by DXA and vibration-controlled transient elastography to assess body composition and liver steatosis and fibrosis, respectively. Multivariable logistic regression analysis was performed to evaluate the contribution of BMI and android:gynoid ratio (A:G ratio) to the prevalence of liver steatosis and fibrosis in males and females., Results: Weighted prevalence of steatosis was 41.5% and 29.9% among the 1115 males and 1113 females included in the study, respectively, whereas 7.0% of males and 4.0% of females had elastographic evidence of significant liver fibrosis. After adjustment for age, race-Hispanic origin, diabetes, cigarette smoke, and BMI, a higher A:G ratio was associated with increased odds of steatosis in both males (OR: 1.79; 95% CI: 1.07, 2.99; P = 0.029) and females (OR: 1.95; 95% CI: 1.11, 3.41; P = 0.023). Conversely, a significant association between A:G ratio and liver fibrosis was identified in females (OR: 2.09; 95% CI: 1.11, 3.97; P = 0.026), but not in males (OR: 0.56; 95% CI: 0.29, 1.08; P = 0.078)., Conclusions: Independently from BMI, an android fat deposition pattern is associated with increased prevalence of NAFLD in both sexes, whereas the effect on fibrosis was only evident in females., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Aims: Soluble Klotho (s-Klotho) is associated with chronic kidney disease (CKD) and aging, but little is known on its relationship with chronic micro- and macro-vascular complications of type 2 diabetes and glycemic control. Here, we evaluate the association between s-Klotho levels, glycemic control and renal function in patients with type 2 diabetes (T2D)., Methods: This is a cross-sectional study including 2989 patients with T2D and available s-Klotho measurements from the 2007-2016 cycles of the National Health and Nutrition Examination Survey (mean ± SE, age: 60.0 ± 0.2 years, BMI 33.3 ± 0.2 kg/m 2 , 46.7 ± 1.3% female). Determination of s-Klotho concentrations was performed with a sandwich ELISA test., Results: Patients with higher s-Klotho levels were younger, more frequently female and had a lower prevalence of CKD and higher HbA1c levels. In multivariable linear regression models adjusting for age, race-ethnicity and BMI, both estimated glomerular filtration rate (B = 2.21, 95% CI 1.41-3.01, p < 0.001) and hemoglobin A1c (B = 37.38, 95% CI 28.91-45.86, p < 0.001) were positively associated with s-Klotho, while no significant association was found with cardiovascular disease. Results were confirmed when analyses were performed in men and women separately. No significant differences were identified between patients with an albuminuric or non-albuminuric CKD phenotype., Conclusions: s-Klotho levels are dependent on kidney function and glycemic control in patients with T2D. Additional studies elucidating the mechanisms linking glycemic control and s-Klotho levels and exploring their predictive ability of clinically meaningful outcomes in patients with diabetes are needed., (© 2022. The Author(s).)

Chronic hepatitis C (CHC) and diabetes represent two severe chronic conditions responsible for a considerable number of deaths worldwide. They have a complex, bidirectional relationship. On the one hand, several cohort studies have shown that chronic HCV infection increases both the risk of developing diabetes in non-diabetic subjects (by inducing insulin resistance and promoting β-cell dysfunction) as well as the risk of developing macro and microvascular complications in patients with known diabetes; on the other hand, diabetes is an independent risk factor for liver-related events among patients with CHC, including a higher incidence of hepatocellular carcinoma, liver-related death and transplantation. Importantly, sustained virological response, which can be obtained in the vast majority of patients with the use of direct antiviral agents, does not only lead to a lower rate of liver-related outcomes, but also to improvements of glycemic control and reduction in the rate of complications among patients with diabetes. The aim of this review is to summarize available clinical evidence on the association among CHC, diabetes and related clinical outcomes. We will also briefly discuss the biological mechanisms underpinning the association between CHC and diabetes, as well as the implications this relationship should have on everyday clinical practice., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Several studies reported an association between nonalcoholic fatty liver disease (NAFLD) and the risk of incident hypertension. The objective of this systematic review and meta-analysis was to obtain a precise and reliable estimate of the nature and magnitude of this association. We systematically searched Ovid-MEDLINE up to March 2021 for observational studies in which NAFLD was diagnosed in adults using blood-based panels, imaging techniques or liver biopsy and with a follow-up ≥1 year. Measures of association from individual studies were meta-analyzed using random-effects models. Of the 1108 titles initially scrutinized, we included 11 cohort studies with data on 390 348 participants (52% male) and a mean follow-up of 5.7 years. In the overall analysis, NAFLD was associated with a moderately increased risk of incident hypertension (hazard ratio 1.66; 95% confidence interval (CI), 1.38-2.01; test for overall effect z = 5.266; P < 0.001). There was significant heterogeneity among the studies (P < 0.001). Sensitivity analyses showed that estimates were not affected by geographical location, duration of follow-up and adjustment for baseline blood pressure values. On the other hand, the magnitude of the association was lower in studies that adjusted for baseline adiposity compared with those that did not, explaining part of the observed heterogeneity. No significant publication bias was detected by funnel plot analysis and Egger's and Begg's tests. This large meta-analysis indicates that NAFLD is associated with a ~1.6-fold increased risk of developing hypertension. Further studies are needed to investigate the role of NAFLD severity in terms of inflammation and fibrosis on incident hypertension., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Obesity represents a well-known risk factor for metabolic-dysfunction associated fatty liver disease (MAFLD) and its progression towards cirrhosis. The aim of this study is to estimate the proportion of potential candidates to a bariatric surgery intervention that has an elevated liver stiffness on vibration-controlled transient elastography (VCTE)., Materials and Methods: This is a cross-sectional study performed using data obtained during the 2017-2018 cycle of the National Health and Nutrition Examination Survey. Potential candidates for a bariatric surgery intervention from the general US population were identified by applying criteria from international guidelines. All included participants were evaluated by VCTE. A controlled attenuation parameter (CAP) value ≥ 288 dB/m was considered indicative of steatosis while liver stiffness measurement (LSM) was considered elevated if ≥ 9.7 kPa. Multivariable logistic regression models were fitted to identify independent predictors of both outcomes., Results: A total of 434 participants were included (mean age 42.9 ± 0.6 years; 54.4% women). Among them, 76.7% (95% CI 71.7-81.0) had steatosis, while 23.1% (95% CI 17.8-29.3) had an elevated LSM. Male sex, older age, γ-glutamyltranspeptidase levels, and body mass index (BMI) were independent predictors of steatosis, while BMI was the only independent predictor of elevated LSM. Non-Hispanic black participants were protected from both outcomes, while other ethnicities were not., Conclusion: The prevalence of elevated LSM is high in potential candidates for a bariatric surgery intervention. Accurate screening for occult advanced liver disease might be indicated in this patient population., (© 2022. The Author(s).)

An association between liver stiffness, a surrogate measure of liver fibrosis, and chronic kidney disease (CKD) in patients with nonalcoholic fatty liver disease (NAFLD) has been proposed. However, most studies were small and had low statistical power. We systematically searched PubMed-MEDLINE and Scopus from inception to August 2021 for cross-sectional or cohort studies reporting the association between liver stiffness diagnosed by vibration controlled transient elastography (VCTE) and renal dysfunction. The primary outcome was CKD, defined as a composite of urinary albumin to creatinine ratio (UACR) ≥ 30 mg/g and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 . Measures of association from individual studies were meta-analyzed using random effects models. Of the 526 titles initially scrutinized, 7 cross-sectional studies fulfilled the criteria and were included. For CKD, risk was higher in patients with liver fibrosis assessed by VCTE, compared with patients without (n = 5 studies: OR 2.49, 95% CI 1.89-3.29; test for overall effect z = 6.475, p < 0.001). When increased UACR was considered as an outcome, elevated liver stiffness was associated with a significantly increased risk as well (n = 3 studies: OR 1. 98 95% CI 1.29-3.05; test for overall effect z = 3.113, p = 0.002). Neither analysis showed significant heterogeneity (I 2 = 0% and I 2 = 46.5%, respectively for the two outcomes). This meta-analysis indicates that elevated liver stiffness is associated with increased odds of kidney outcomes among patients with NAFLD. Wider use of VCTE to screen for advanced fibrosis might help identify patients at risk of end-stage renal disease.

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult world population and the degree of liver fibrosis represents the best predictor of the development of liver-related outcomes. Easily applicable and well performing non-invasive fibrosis tests can overcome the limitations of liver biopsy and are of paramount importance to identify at-risk subjects in clinical practice. While tests with optimal performance and ease of use do not exist at this stage, available markers can be divided in three broad groups: simple serum tests, complex serum tests and elastographic methods. Simple scores (such as Fibrosis-4 and NAFLD Fibrosis Score) are based on readily available biochemical data and clinical features, while complex/proprietary tests (such as Fibrotest, Enhanced Liver Fibrosis and Hepascore) directly measure markers of fibrogenesis and fibrolysis, but have higher costs. Elastography techniques estimate the degree of fibrosis from liver stiffness and are based on either ultrasound or magnetic resonance (MR) imaging. MR elastography has better performance compared with sonographic techniques and is not affected by obesity and inflammation, but is highly costly and less available. In general, non-invasive tests are able to exclude the presence of fibrosis, but their positive predictive value is low to moderate and they lead to a high number of indeterminate results. In this context, a combination of different tests might increase accuracy while reducing gray-zone results. Their ability to predict future events and response to treatment is suboptimal and needs to be studied further. Finally, recent studies have tried different approaches, spanning from "omics" to the microbiome and micro-RNAs, with some promising results., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: To validate a set of indicators for monitoring the quality of care of patients with diabetes in 'real-life' practice through its relationship with measurable clinical outcomes and healthcare costs., Methods and Results: A population-based cohort study was carried out by including the 20,635 patients, residents in the Lombardy Region (Italy), who in the year 2012 were newly taken-in-care for diabetes. Adherence with clinical recommendations (i.e., controls for glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine) was recorded during the first year after the patient was taken-in-care, and categorized according whether he/she complied with none or almost none (0 or 1), just some (2) or all or almost all (3 or 4) the recommendations, respectively denoted as poor, intermediate and high adherence. Short- and long-term complications of diabetes, and healthcare cost incurred by the National Health Service, were assessed during follow-up. Compared with patients with poor adherence, those with intermediate and high adherence respectively showed (i) a delay in outcome occurrence of 13 days (95% CI, -2 to 27) and 23 days (9-38), and (ii) a lower healthcare cost of 54 € and 77 €. In average, a gain of 18 Euros and 15 Euros for each day free from diabetic complication by increasing adherence respectively from poor to intermediate and from poor to high were observed., Conclusion: Close control of patients with diabetes through regular clinical examinations must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes., Competing Interests: Declaration of competing interest Giovanni Corrao received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part to a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as member of Advisory Board from Roche. Giuseppe Mancia received honoraria for participation as speaker/chairman in national/international meetings from Bayer, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini Int., Merck, Novartis, Recordati and Servier. Other authors declare that they have no conflict of interest to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: To assess and compare the persistence with drug therapy between patients treated with glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2-I) therapy., Methods: The 126,493 residents of the Lombardy Region (Italy) aged ≥ 40 years newly treated with metformin during 2007-2015 were followed until 2017 to identify those who started therapy with GLP1-RA or SGLT2-I. To make GLP1-RA and SGLT2-I users more comparable, a 1:1 matched cohort design was adopted. Matching variables were sex, age, and adherence to the first-line therapy with metformin. Log-binomial regression models were fitted to estimate the propensity to 1-year treatment persistence in relation to the therapeutic strategy., Results: The final matched cohort was composed by 1,276 GLP1-RA─SGLT2-I pairs. About 24% and 29% of cohort members respectively on GLP1-RA and SGLT2-I discontinued the drug treatment. Compared with patients starting SGLT2-I, those on GLP1-RA had 15% (95% confidence interval, 3-25%) lower risk of discontinuation of the treatments of interest and 45% (28-57%) lower risk of discontinuing any antidiabetic drug therapy. Persistence was better among GLP1-RA users who received a once-weekly administration., Conclusions: In a real-life setting, patients who were prescribed a GLP1-RA exhibited more frequently better persistence to treatment than those prescribed a SGLT2-I therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giovanni Corrao received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part to a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as member of Advisory Board from Roche. Other authors declare that they have no conflict of interest to disclose., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

[Figure: see text].