Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Once-weekly semaglutide use in patients with type 2 diabetes: Results from the SURE France multicentre, prospective, observational study.

AIMS: Real-world data are required to support glucagon-like peptide-1 receptor agonist use in type 2 diabetes (T2D). SURE France assessed once-weekly semaglutide in adults with T2D in real-world clinical practice. MATERIALS AND METHODS: This multicentre, prospective, open-label, single-arm study included adults with T2D and ≥1 documented glycated haemoglobin (HbA1c) value ≤12 weeks before semaglutide initiation. The primary endpoint was HbA1c change from baseline to end of study (EOS; ~30 weeks). Secondary endpoints included change from baseline to EOS in body weight (BW) and waist circumference (WC); and proportion achieving HbA1c targets. Baseline characteristics and safety were reported for the full analysis set (patients initiating semaglutide). Analysis of other endpoints was based on the effectiveness analysis set (study completers receiving semaglutide at EOS). RESULTS: Of 497 patients initiating semaglutide (41.6% female, mean age 58.3 years), 348 completed the study on treatment. Baseline HbA1c, diabetes duration, BW and WC, were 8.3%, 10.0 years, 98.2 kg and 114.2 cm, respectively. The most common reasons for initiating semaglutide were to improve glycaemic control (79.7%), reduce BW (69.8%) and address cardiovascular risk (24.1%). At EOS, mean changes were: HbA1c, -1.2% points [95% confidence interval (CI) -1.32; -1.10]; BW, -4.7 kg (95% CI -5.38; -4.07); and WC, -4.9 cm (95% CI -5.94; -3.88). At EOS, 81.7%, 67.7% and 51.6% of patients achieved an HbA1c target of <8.0%, <7.5% and <7.0%, respectively. No new safety concerns were identified. CONCLUSIONS: These results support the benefits of semaglutide in a real-world setting in adults with T2D in France showing a significant reduction in HbA1c and body weight.

Once-weekly semaglutide use in patients with type 2 diabetes: Real-world data from the SURE Italy observational study.

AIMS: SURE Italy, a multicentre, prospective, open-label, observational, real-world study, investigated once-weekly semaglutide in patients with type 2 diabetes (T2D) in routine clinical practice. MATERIALS AND METHODS: Adults with T2D and ≥1 documented glycated haemoglobin (HbA1c) level within 12 weeks of semaglutide initiation were enrolled. The primary endpoint was change in HbA1c from baseline to end of study (EOS; ~30 weeks). Other endpoints included changes in body weight, waist circumference and patient-reported outcomes, and the proportion of patients achieving HbA1c <7.0% or <6.5%, weight loss ≥5% and a post-hoc composite endpoint (HbA1c reduction of ≥1%-point and weight loss ≥5%). These endpoints were reported for patients on semaglutide at EOS [effectiveness analysis set (EAS)]. Safety data were reported in the full analysis set. RESULTS: Of 579 patients who initiated semaglutide (full analysis set), 491 completed the study on treatment (EAS). Mean baseline HbA1c was 8.0%, and 20.7% (120 of 579) of patients had HbA1c <7.0%. Mean semaglutide dose at EOS was 0.66 ± 0.28 mg. In the EAS, mean HbA1c and body weight decreased by 1.1%-point (95% confidence interval 1.20, 1.05; P < .0001) and 4.2 kg (95% confidence interval 4.63, 3.67; P < .0001), respectively. At EOS, 61.7% and 40.8% of patients achieved HbA1c <7.0% and <6.5%, respectively, 40.5% achieved weight loss ≥5% and 25.3% achieved the post-hoc composite endpoint. Patient-reported outcomes improved from baseline to EOS. No new safety concerns were identified. CONCLUSIONS: In routine clinical practice in Italy, patients with T2D treated with once-weekly semaglutide for 30 weeks achieved clinically significant improvements in HbA1c, body weight and other outcomes.

Real-World Use of Once-Weekly Semaglutide in Type 2 Diabetes: Results from SemaglUtide Real-world Evidence (SURE) Germany.

CONTEXT: Efficacy and safety of once-weekly semaglutide in type 2 diabetes were established in the phase 3 SUSTAIN trials, which included patients across the continuum of type 2 diabetes care. It is useful to complement these findings with real-world evidence. OBJECTIVE: SURE Germany evaluated once-weekly semaglutide in a real-world type 2 diabetes patient population. DESIGN/SETTING: The prospective observational study was conducted at 93 clinical practices in adults with+≥ 1 documented glycated haemoglobin value ≤12 weeks before initiation of semaglutide. INTERVENTION: Once-weekly semaglutide was prescribed at the physicians' discretion. MAIN OUTCOMES: The primary endpoint was change in glycated haemoglobin from baseline to end-of-study (~30 weeks). Secondary endpoints included changes in body weight and patient-reported outcomes. All adverse events were systematically collected and reported, including patient-reported documented and/or severe hypoglycaemia. RESULTS: Of 779 patients in the full analysis set, 669 (85.9%) completed the study on treatment with semaglutide, comprising the effectiveness analysis set. In this data set, estimated mean changes in glycated haemoglobin and body weight from baseline to end-of-study were -1.0%point (-10.9 mmol/mol; P<0.0001) and -4.5 kg (-4.2%; P<0.0001). Sensitivity analyses supported the primary analysis. Improvements were observed in other secondary endpoints, including patient-reported outcomes. No new safety concerns were identified. CONCLUSIONS: In a real-world population in Germany, patients with type 2 diabetes treated with once-weekly semaglutide experienced clinically significant improvements in glycaemic control and body weight. These results support the use of once-weekly semaglutide in routine clinical practice in adult patients with type 2 diabetes in Germany.

Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study.

Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (-0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3 : 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3 : 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.

Body mass index in childhood and adult risk of primary liver cancer.

BACKGROUND & AIMS: Childhood overweight increases the risk of early development of non-alcoholic fatty liver disease, which may predispose to carcinogenesis. We investigated if childhood body size during school ages was associated with the risk of primary liver cancer in adults. METHODS: A cohort of 285,884 boys and girls, born 1930 through 1980, who attended school in Copenhagen, were followed from 1977 to 31 December 2010. Their heights and weights were measured by school doctors or nurses at ages 7 through 13 years. Body mass index (BMI) z-scores were calculated from an internal age- and sex-specific reference. Information on liver cancer was obtained from the National Cancer Registry. Hazard ratios and 95% confidence intervals (95% CI) of liver cancer were estimated by Cox regression. RESULTS: During 6,963,105 person-years of follow-up, 438 cases of primary liver cancer were recorded. The hazard ratio (95% CI) of adult liver cancer was 1.20 (1.07-1.33) and 1.30 (1.16-1.46) per 1-unit BMI z-score at 7 years and 13 years of age, respectively. Similar associations were found in boys and girls, for hepatocellular carcinoma only, across years of birth, and after accounting for diagnoses of viral hepatitis, alcohol-related disorders, and biliary cirrhosis. CONCLUSIONS: Higher BMI in childhood increases the risk of primary liver cancer in adults. In view of the high case fatality of primary liver cancer, this result adds to the future negative health outcomes of the epidemic of childhood overweight, reinforcing the need for its prevention.

Interaction between obesity and the NFKB1 - 94ins/delATTG promoter polymorphism in relation to incident acute coronary syndrome: a follow up study in three independent cohorts.

INTRODUCTION: The NF-κB transcription factor family regulates several genes encoding pro-inflammatory and anti-inflammatory proteins in adipose tissues and in atherosclerotic plaques. The deletion variant allele of the NFKB1 - 94ins/delATTG promoter polymorphism leads to lower transcript levels of the p50 subunit, and the variant allele has been associated with the risk of several inflammatory diseases as well as coronary heart disease where inflammation is important in the pathogenesis. The objective of this study was to explore the potential interaction between the NFKB1-94ins/delATTG promoter polymorphism and general, abdominal, and gluteofemoral obesity in relation to the risk of incident acute coronary syndrome (ACS) in three large independent cohorts. METHODS AND RESULTS: The analyses were conducted in the Danish prospective study Diet, Cancer and Health and the two US based cohorts; Nurses' Health Study and Health Professionals Follow-up Study. We conducted sex stratified analyses that included 1202 male and 708 female cases of incident ACS. We observed a positive association for general and abdominal obesity with risk of incident ACS, independent of genotype in both genders. Gluteofemoral obesity was negatively associated with ACS risk in women independent of genotype, whereas there was no clear association for men. We calculated the relative excess risk due to interaction (RERI) and observed a statistically significant excess risk among men jointly exposed to general or abdominal obesity and the variant allele of the NFKB1-94ATTG polymorphism, whereas there was a tendency towards sub-additivity for gluteofemoral obesity. The excess risks in all analyses were, however, small and could not clearly be demonstrated in women. CONCLUSION: The variant allele of the NFKB1-94ins/delATTG promoter polymorphism did not substantially modify the association between obesity and incident ACS.

Waist circumference adjusted for body mass index and intra-abdominal fat mass.

BACKGROUND: The association between waist circumference (WC) and mortality is particularly strong and direct when adjusted for body mass index (BMI). One conceivable explanation for this association is that WC adjusted for BMI is a better predictor of the presumably most harmful intra-abdominal fat mass (IAFM) than WC alone. We studied the prediction of abdominal subcutaneous fat mass (ASFM) and IAFM by WC alone and by addition of BMI as an explanatory factor. METHODOLOGY/PRINCIPAL FINDINGS: WC, BMI and magnetic resonance imaging data from 742 men and women who participated in clinical studies in Canada and Finland were pooled. Total adjusted squared multiple correlation coefficients (R(2)) of ASFM and IAFM were calculated from multiple linear regression models with WC and BMI as explanatory variables. Mean BMI and WC of the participants in the pooled sample were 30 kg/m(2) and 102 cm, respectively. WC explained 29% of the variance in ASFM and 51% of the variance in IAFM. Addition of BMI to WC added 28% to the variance explained in ASFM, but only 1% to the variance explained in IAFM. Results in subgroups stratified by study center, sex, age, obesity level and type 2 diabetes status were not systematically different. CONCLUSION/SIGNIFICANCE: The prediction of IAFM by WC is not improved by addition of BMI.

Changes in waist circumference and the incidence of acute myocardial infarction in middle-aged men and women.

BACKGROUND: Waist circumference (WC) measured at one point in time is positively associated with the risk of acute myocardial infarction (MI), but the association with changes in WC (DWC) is not clear. We investigated the association between DWC and the risk of MI in middle-aged men and women, and evaluated the influence from concurrent changes in BMI (DBMI). METHODOLOGY/PRINCIPAL FINDINGS: Data on 38,593 participants from the Danish Diet, Cancer and Health study was analysed. Anthropometry was assessed in 1993-97 and 1999-02. Information on fatal and non-fatal MI was obtained from National Registers. Cases were validated by review of the medical records. Hazard ratios (HR) were calculated from Cox proportional hazard models with individuals considered at risk from 1999-02 until December 30 2009. During 8.4 years of follow-up, 1,041 incident cases of MI occurred. WC was positively associated with the risk of MI, but weakly after adjustment for BMI. DWC was not associated with the risk of MI (HR per 5 cm change = 1.01 (0.95, 1.09) with adjustment for covariates, baseline WC, BMI and DBMI). Associations with DWC were not notably different in sub-groups stratified according to baseline WC or DBMI, or when individuals with MI occurring within the first years of follow-up were excluded. CONCLUSIONS/SIGNIFICANCE: WC was positively associated with the risk of MI in middle-aged men and women, but changes in WC were not. These findings suggest that a reduction in WC may be an insufficient target for prevention of MI in middle-aged men and women.

Changes in waist circumference and the incidence of diabetes in middle-aged men and women.

BACKGROUND: Waist circumference (WC) is positively associated with diabetes, but the association with changes in WC (DWC) is less clear. We investigated the association between DWC and the subsequent risk of diabetes in middle-aged men and women, and evaluated the influence from concurrent changes in body mass index (DBMI). METHODOLOGY/PRINCIPAL FINDINGS: Data on 15,577 men and 20,066 women from the Danish Diet, Cancer and Health study were analyzed. Anthropometry was assessed in 1993-97 and 1999-02. Information on diabetes was obtained from The Danish National Diabetes Register. Hazard ratios (HR) were calculated from Cox' proportional hazard models with individuals considered at risk from 1999-02 until December 31 2006. During 5.4 years of follow-up, 1,027 and 876 new cases of diabetes occurred among men and women, respectively. WC was positively associated with diabetes in both sexes also with adjustment for covariates and BMI. DWC was positively associated with diabetes in women, but not in men (HR per 5 cm change = 1.09 (1.04:1.15) in women, and 1.00 (0.94, 1.07) in men with adjustment for covariates, baseline WC, BMI and DBMI). Associations with DWC were not notably different in sub-groups stratified according to baseline WC or DBMI, or when individuals with diseases or diabetes occurring within the first years of follow-up were excluded. CONCLUSIONS/SIGNIFICANCE: While this study confirmed that WC is positively associated with the risk of diabetes in middle-aged men and women, it surprisingly showed that changes in WC were not associated with the subsequent risk of diabetes in men, and only weakly positively associated with the risk of diabetes in women. Accordingly, these findings suggest that a reduction in WC may be a weak or insufficient or target for prevention of diabetes in middle-aged men and women.

Changes in waist circumference and mortality in middle-aged men and women.

BACKGROUND: Waist circumference (WC) adjusted for body mass index (BMI) is positively associated with mortality, but the association with changes in WC is less clear. We investigated the association between changes in WC and mortality in middle-aged men and women, and evaluated the influence from concurrent changes in BMI. METHODOLOGY/PRINCIPAL FINDINGS: Data on 26,625 healthy men and women from the Danish Diet, Cancer and Health study was analyzed. WC and BMI were assessed in 1993-97 and in 1999-02. Information on mortality was obtained by linkage to the Danish central Person Register. Hazard ratios (HR) were estimated with Cox regression models. During 6.7 years of follow-up, 568 and 361 deaths occurred among men and women, respectively. Changes in WC were positively associated with mortality (HR per 5 cm for the sexes combined  = 1.09 (1.02 : 1.16) with adjustment for covariates, baseline WC, BMI and changes in BMI), whereas changes in BMI were inversely associated with mortality (HR per kg/m2 for the sexes combined  = 0.91 (0.86, 0.97) with adjustment for covariates, baseline WC, BMI and changes in WC). Associations between changes in WC and mortality were not notably different in sub-groups stratified according to changes in BMI, baseline WC or when smokers or deaths occurring within the first years of follow-up were excluded. CONCLUSIONS/SIGNIFICANCE: Changes in WC were positively associated with mortality in healthy middle-aged men and women throughout the range of concurrent changes in BMI. These findings suggest a need for development of prevention and treatment strategies targeted against redistribution of fat mass towards the abdominal region.