BMJ Open Diabetes Research & Care最新文献

Introduction: The prevalence of type 2 diabetes (T2D) has surged, yet body mass index (BMI) fails to explain the 30%-40% of cases that occur in individuals with a healthy weight. Emerging evidence suggests that regional fat distribution differentially impacts glucose metabolism, independent of total adiposity. This study investigated the independent association between regional body composition and T2D risk using BMI-matched National Health and Nutrition Examination Survey (NHANES) data to identify sex-specific effects and the mediating role of insulin resistance.

Research design and methods: Our study employed data from the 2011-2018 cycles of NHANES. Participants were classified into a high-risk T2D group if they met one or more of the following criteria: fasting blood glucose≥6.1 mmol/L, 2-hour blood glucose≥7.8 mmol/L following an oral glucose tolerance test or self-reported physician's diagnosis of diabetes or pre-diabetes. Body composition data were assessed via dual-energy X-ray absorptiometry, which provides a precise assessment of regional fat and muscle mass distribution.

Results: Participants at high T2D risk exhibited significantly reduced lower limb fat mass compared with healthy controls (p<0.001), with higher amounts of lower limb fat serving as a protective factor against both diabetes and insulin resistance. Notably, this protective effect of lower-limb fat (OR 0.86 (0.76-0.97), p=0.01) along with the detrimental impact of visceral fat (OR 7.35 (1.57-34.4), p=0.01) was particularly pronounced in male subjects. Additionally, 36.18% of the protective effect of lower limb fat on diabetes is mediated by improved insulin sensitivity.

Conclusions: This study delineates a protective role for lower-body fat in diabetes pathogenesis, mediated substantially through ameliorating insulin resistance. The sex-specific associations underscore the protective effect of lower-body fat and the detrimental impact of visceral adiposity in men after controlling for BMI.

Introduction: Hepatic fibrosis caused by metabolic dysfunction-associated steatotic liver disease (MASLD) predicts adverse atherosclerotic cardiovascular disease (ASCVD) outcomes in the general patient population. However, it is unclear whether this association extends to type 2 diabetes mellitus (T2DM) patients, who have distinct metabolic profiles and high comorbidity of both MASLD and ASCVD. To address this gap, we investigated the association between hepatic fibrosis caused by MASLD and ASCVD risk in T2DM patients as well as potentially moderators of this association.

Research design and methods: This multisite cross-sectional study included 1238 hospitalized T2DM patients with MASLD (mean age=57.81±10.23, 37% female). Hepatic fibrosis was assessed via the Steatosis-Associated Fibrosis Estimator (SAFE) score, and 10-year ASCVD risk was assessed via the ASCVD Risk Calculator.

Results: Advanced fibrosis was present in 25.6% of patients. Multivariable regression revealed a significant association between the SAFE score and 10-year ASCVD risk (p<0.001), after adjusting for covariates. Each unit increase in SAFE score was associated with 0.07-unit increase in 10-year ASCVD risk score. Increase in SAFE score was associated with greater increase in 10-year ASCVD risk score among patients with hypertension, insulin resistance and elevated low-density lipoprotein (LDL) cholesterol (ps<0.05). Overweight/obesity, triglycerides, high-density lipoprotein cholesterol, uric acid, thyroid-stimulating hormone, hemoglobin A1c and high-sensitivity C reactive protein showed no moderating effects.

Conclusions: In T2DM patients, hepatic fibrosis caused by MASLD is associated with elevated ASCVD risks, particularly among those with hypertension, insulin resistance and elevated LDL cholesterol. It is crucial to incorporate hepatic fibrosis assessment into ASCVD risk stratification in T2DM patients with comorbid MASLD to inform early prevention of ASCVD.

Introduction: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME.

Research design and methods: This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis.

Results: The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02).

Conclusions and relevance: We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.

Introduction: Prediabetes presents an opportunity for early intervention. Growing evidence suggests that psychological stress may contribute to glucose dysregulation, but the findings are inconsistent.This study aimed to clarify the association between perceived stress and glycemic measures, by first testing gender as a moderator, and then examining age as a moderator within each gender group.

Research design and methods: We analyzed cross-sectional data from 470 diabetes-free adults in Singapore. Participants completed the 10-item Perceived Stress Scale, comprising two subscales: perceived helplessness and perceived self-efficacy. Glycemic measures included fasting plasma glucose, glycated hemoglobin, and 2-hour plasma glucose (2h-PG) following an oral glucose tolerance test. Prediabetes was classified according to the American Diabetes Association diagnostic criteria.

Results: Multivariable regression analyses revealed significant moderating effects of gender on the relationship between perceived stress factors and both prediabetes status and 2h-PG levels. Specifically, higher perceived helplessness and perceived self-efficacy were significantly associated with a lower prevalence of prediabetes and lower 2h-PG levels among men. However, these associations were non-significant among women. Age significantly moderated the relationship between perceived helplessness (but not perceived self-efficacy) on prediabetes and 2h-PG levels in women; higher perceived helplessness was associated with a greater prevalence of prediabetes and higher 2h-PG levels among younger women.

Conclusions: Gender moderated the associations between perceived stress and both prediabetes prevalence and 2h-PG levels. Among women, age further moderated the association between perceived helplessness and these outcomes. Future research should consider both moderators. Tailored psychosocial stress management strategies may help reduce the prevalence of prediabetes and diabetes.

Trial registration number: NCT02838693.

Introduction: Hemoglobin A1c (A1c) treatment goals in older adults often consider life expectancy and comorbidities. A1c stability may also inform the risks of major outcomes. We studied the association of individualized A1c time-in-range (A1c TIR) with mortality and diabetes complications.

Research design and methods: We conducted a retrospective observational cohort study of patients with diabetes, 65 years or older, from the Department of Veterans Affairs (VA) and Kaiser Permanente (KP) from 2004 to 2018. Patients had at least four A1c tests during a 3-year baseline, and A1c TIR was calculated as the percentage of days when A1c levels were within patient-specific target ranges. We estimated associations among A1c TIR and mortality, cardiovascular, and microvascular outcomes using time to event models and instrumental variable (IV) models.

Results: We identified 386 287 VA patients and 24 885 KP patients with a mean age of 74.3 years (SD 5.8) and 72.3 years (SD 5.7), respectively. Among VA patients, when compared with higher A1c TIR (80-100%), lower A1c TIR (0% to <20%) was associated with increased mortality (HR, 1.22; 95% CI 1.20 to 1.23) and cardiovascular outcomes (HR, 1.10; 95% CI 1.07 to 1.13). IV models showed similar associations. Among KP patients, lower A1c TIR (0% to <20%) was associated with mortality (HR, 1.36; 95% CI 1.27 to 1.45). IV models showed associations with increased mortality and cardiovascular outcomes. Among both VA and KP patients, greater A1c time below and time above range were associated with increased mortality.

Conclusions: A1c stability within patient-specific target ranges is associated with a lower risk of major adverse outcomes among older adults with diabetes.

Objective: Using national claims databases, we sought to emulate the design of the ongoing SEPRA trial and predict its findings, comparing the effects of once weekly semaglutide to SoC medications on glycemic control (A1C <7%) in type-2 diabetes mellitus (T2D).

Research design and methods: Using Optum Clinformatics (July 2017 - May 2022), we identified a 1:1 propensity score-matched (PSM) cohort of adults with T2D on metformin monotherapy, who had recorded A1C and initiated either injectable semaglutide or SoC medications (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, SUs, or glucagon-like peptide-1 agonists) and met eligibility criteria adapted from the SEPRA trial. The primary outcome was the proportion of patients achieving A1C <7%. The study protocol was preregistered (NCT05577728, ClinicalTrials.gov) before any etiologic analyses. Risk ratios and corresponding 95% CIs were estimated.

Results: We identified 1,144 PSM pairs of injectable semaglutide and SoC initiators with balance in pre-exposure covariates. Semaglutide initiators were 30% (risk ratio (95% CI), 1.30 (1.16 to 1.45)) more likely to achieve glycemic control (A1C <7%) than those initiating SoC. Additionally, semaglutide initiators had a 1.3% reduction in A1C, compared with a 1.1% reduction in the SoC group. These results were consistent with interim results of the SEPRA trial, which were released after the protocol for our database study was preregistered.

Conclusion: This claims database study, designed to predict the results of the SEPRA trial, found results consistent with interim trial results. Our findings support the notion that well-designed non-randomized studies using fit-for-purpose data can effectively complement pragmatic randomized controlled trials.

Introduction: This study aims to investigate the association between change in urine albumin-to-creatinine ratio (UACR) and clinical outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes.

Research design and methods: Adult patients with elevated UACR (≥30 mg/g in initial testing) after the diagnosis of type 2 diabetes and CKD were identified from the Optum electronic health records database (01/2007-09/2021). UACR change from initial to last test (6-24 months) was categorized as >30% decrease, stable (-30% to 30%), or >30% increase. Risk of all-cause mortality, composite cardiovascular (CV) outcome (CV death, myocardial infarction, stroke, and hospitalization for heart failure), and CKD progression (≥40% decline in estimated glomerular filtration rate or kidney failure) were estimated with Cox proportional hazard models adjusted for baseline characteristics.

Results: Compared with patients with a stable UACR (n=35 117), those with a >30% UACR decrease (n=89 562) had lower risk of all-cause mortality (adjusted HR (aHR)=0.93, 95% CI 0.90 to 0.96), composite CV outcomes (aHR=0.93, 95% CI 0.90 to 0.95), and CKD progression (aHR=0.84, 95% CI 0.81 to 0.86) (all p<0.001), and patients with a >30% UACR increase (n=35 703) had higher risk of each endpoint (aHR=1.24, 95% CI 1.19 to 1.28; aHR=1.24, 95% CI 1.20 to 1.28; and aHR=1.41, 95% CI 1.36 to 1.46, respectively; all p<0.001).

Conclusions: In patients with CKD and type 2 diabetes, a >30% UACR decrease was associated with lower risk of mortality, CV events, and CKD progression, whereas a >30% UACR increase was associated with higher risk of these clinical outcomes. These findings highlight the importance of albuminuria monitoring and potential clinical benefits of targeted UACR reductions in this population.

Introduction: This study evaluated the long-term effectiveness of once-weekly subcutaneous semaglutide versus alternative treatment in adults with type 2 diabetes (T2D) in routine clinical practice.

Research design and methods: The SEmaglutide PRAgmatic (SEPRA) was a 2-year, randomized, open-label, pragmatic clinical trial (NCT03596450). Adults with T2D and inadequate glycemic control on one or two oral antidiabetic medications were randomized to receive once-weekly subcutaneous semaglutide or alternative treatment (chosen by the treating physician) as add-on therapy. Endpoints included proportion of participants achieving glycated hemoglobin (HbA_1c)<7.0% at year 1 (primary endpoint) and year 2; changes in HbA_1c (percentage point), body weight, and patient-reported outcomes (PROs) at years 1 and 2; and treatment changes (baseline to year 2). Missing data were imputed for some analyses.

Results: Participants were randomized to semaglutide (n=644) or alternative treatment (n=634). Proportions of participants achieving HbA_1c <7.0% were significantly higher with semaglutide versus alternative treatment at years 1 (53.1% vs 45.5%; OR (95% CI): 1.36 (1.03 to 1.79); p=0.033) and 2 (49.9% vs 38.9%; OR (95% CI): 1.56 (1.13 to 2.16); p=0.007). Mean HbA_1c decreases were larger with semaglutide versus alternative treatment at year 1 (-1.35% vs -1.16%; estimated treatment difference (ETD) (95% CI): -0.20% (-0.39% to 0.00%); p=0.046) and year 2 (-1.27% vs -0.96%; ETD (95% CI): -0.31% (-0.57% to -0.05%); p=0.018). Semaglutide was associated with larger reductions in body weight at year 1 (-3.57% vs -1.91%; ETD (95% CI): -1.65% (-2.92% to -0.39%); p=0.010) but not year 2 (p=0.175). Treatment changes occurred less frequently with semaglutide than with alternative treatments. Some PROs indicated greater improvement with semaglutide versus alternative treatment. No new safety concerns were identified.

Conclusions: SEPRA demonstrates that semaglutide is an appropriate choice for treatment intensification among individuals with T2D in the USA who are receiving 1-2 antidiabetic medications. Findings support semaglutide as an effective and well-tolerated option in clinical practice.

Trial registration number: NCT03596450.

Introduction: This study investigated the incidence of diabetic retinopathy (DR) and sight-threatening DR (STDR) through 2021 in patients diagnosed with type 2 diabetes (T2DM) in 1996-2004. The study also investigated risk factors associated with DR.

Research design and methods: The cohort comprised patients in the Swedish Skaraborg Diabetes Register in 1996-2004 who were ≤70 years at T2DM diagnosis and without DR at first-eye examination. Clinical data at diagnosis included age, smoking habits, body mass index, blood pressure, HbA1c, high-density lipoprotein cholesterol, triglycerides, c-peptide and antihypertensive drugs as a proxy for hypertension. The level of DR at first eye examination after diagnosis through 31 December 2021 was extracted from medical records at the Department of Ophthalmology, Skaraborg Hospital. The cumulative incidence of DR was estimated by the Kaplan-Meier method, and multivariate Cox regression models were used to estimate the risk of DR.

Results: The study included 2267 patients; over the course of 24 years of follow-up (mean 12.8±5.8 years), 926 developed DR and 101 developed STDR. The cumulative incidence after 10 and 20 years was 29.0% and 67.6% for DR and 1.4% and 11.4% for STDR. Higher HbA1c (HR 1.02 per 1 mmol/mol, 95% CI 1.01 to 1.02) and antihypertensive treatment at diagnosis (HR 1.26, 95% CI 1.08 to 1.47) were associated with increased risk of DR. Higher age (HR 0.98 per year, 95% CI 0.97 to 0.98) and diagnosis in 1999-2004 versus 1996-1998 (HR 0.58, 95% CI 0.51 to 0.66) were associated with a lower risk of DR.

Conclusion: During follow-up, 926 patients developed DR, whereas 101 developed STDR. Higher HbA1c and antihypertensive treatment were associated with a higher risk of developing DR and STDR, while higher age at diagnosis and diagnosis in 1999-2004 versus 1996-1998 were associated with lower risk.