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Aims: To develop and externally validate the LIFE‐T1D model for the estimation of lifetime and 10‐year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. Materials and Methods: A sex‐specific competing risk‐adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non‐high‐density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. Results: During a median follow‐up of 11.8 years (interquartile interval 6.1–17.1 years), 4608 CVD events and 1316 non‐CVD deaths were observed in the NDR (n = 39 756). The internal validation c‐statistic was 0.85 (95% confidence interval [CI] 0.84–0.85) and the external validation c‐statistics were 0.77 (95% CI 0.74–0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70–0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. Conclusions: The LIFE‐T1D model can estimate lifetime risk of CVD and CVD‐free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between lactation and maternal risk of type 2 diabetes, including a potential graded association according to lactation duration. Methods: A systematic review and meta‐analysis of observational studies that investigated the reported association between lactation (irrespective of duration, intensity or mode) and maternal risk of type 2 diabetes was conducted. Results: A total of 22 studies (17 cohort studies and five cross‐sectional studies) were included in this systematic review, and 16 contributed to the meta‐analysis. Studies that investigated the association of lactation with risk of type 2 diabetes in the first months after birth in women with gestational diabetes reported conflicting results. Studies with a longer follow‐up showed a graded protective association for lactation and the risk of type 2 diabetes, with a potentially larger risk reduction in women with gestational diabetes than in those without gestational diabetes. Overall, ever versus never lactation was associated with a 27% lower risk of type 2 diabetes (RR 0.73, 95% CI [0.65, 0.83]). Each additional month of lactation was associated with a 1% lower risk of type 2 diabetes (RR 0.99, 95% CI [0.98, 0.99]). However, the overall quality of the studies was modest. Conclusions: Lactation is associated with a significantly reduced risk of maternal type 2 diabetes over the life course, particularly in women with gestational diabetes. The protective effect seems to increase with longer duration of lactation. Further research is warranted to understand whether this association is modified by exposure to other risk factors. [ABSTRACT FROM AUTHOR]

Aim: To estimate the associations between risk factors and cognitive decline (CD)/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death. Materials and Methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression. Results: During a median 5‐year follow‐up, 1827 participants (43.2% women) had CD/dementia (1718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had lower odds of CD/dementia than men (odds ratio [OR] [95% confidence interval], 0.88 [0.77, 1.00]); older age, higher total cholesterol, HbA1c, waist circumference, waist‐to‐height ratio, moderately increased albumin‐creatinine ratio, stroke/transient ischaemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women‐to‐men ratio of ORs [ROR], 1.05 [1.00, 1.10] per 5 cm) and presence of anxiety/depression (ROR, 1.28 [1.01, 1.63]) were associated with greater ORs for CD/dementia in women than men. Conclusions: Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms that underlie these sex differences. [ABSTRACT FROM AUTHOR]

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20‐month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR: low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all‐cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow‐up of 2.9 years following the 20‐month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20‐month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91–1.27 and 1.22, 95% CI: 1.03–1.45, respectively) with evidence of a positive linear trend (p =.015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D. [ABSTRACT FROM AUTHOR]

Aims: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients' characteristics in the older patient group. Materials and Methods: The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140). Results: Over a median follow‐up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82‐0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all‐cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses. Conclusions: Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients. [ABSTRACT FROM AUTHOR]

Obesity is associated with severe COVID‐19 outcomes, yet, it is unclear whether the risk of COVID‐19 mortality associated with obesity is similar between the sexes. We used data from the UK Biobank to assess the risk of COVID‐19 mortality associated with various anthropometric measures in women and men. To put these results in context, we also compared these estimates with those for mortality from influenza/pneumonia and coronary heart disease (CHD). The analyses included 502 493 individuals (54% women), of whom 410 (36% women) died from COVID‐19, 549 (36% women) died from influenza/pneumonia and 3355 (19% women) died from CHD. A higher body mass index (BMI), waist circumference, waist‐to‐hip ratio and waist‐to‐height ratio were each associated with a greater risk of death from COVID‐19, influenza/pneumonia and CHD in both sexes, with the exception of the association between higher BMI and the risk of influenza/pneumonia death in men. A higher BMI was associated with a stronger risk of COVID‐19 mortality in women than men; the women‐to‐men ratio of hazard ratios was 1.20 (95% confidence interval 1.00; 1.43). This study demonstrates the role of obesity in COVID‐19 mortality and shows that the relative effects of a higher BMI on COVID‐19 mortality may be stronger in women than men. [ABSTRACT FROM AUTHOR]

Aim: To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large‐scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. Materials and methods: Eleven thousand and sixty‐five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post‐trial follow‐up study, ADVANCE‐ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non‐fatal) by sex, and the women‐to‐men ratio of HRs (RHR). Results: Over a median of 9.6 years of follow‐up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05‐2.91) for current smoking, 1.53 (1.00‐2.32) for former smoking, 1.18 (1.02‐1.37) for SBP, and 1.13 (95% CI, 1.003‐1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person‐years) compared with women (5.8 per 1000 person‐years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. Conclusions: In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex‐specific approaches and early interventions in women with diabetes. [ABSTRACT FROM AUTHOR]

Aims: To explain, and document, the epidemiological work associated with the action in diabetes and vascular disease: preterax and diamicron‐modified release controlled evaluation (ADVANCE) clinical trial. Materials and methods: ADVANCE was designed as a randomized controlled multicentre factorial trial in high‐risk patients with diabetes. The two interventions were blood pressure lowering medications versus placebo, and intensive glucose control versus standard glucose control. Following termination of the trial, an observational study of surviving participants, able to join, was mounted: the ADVANCE ‐ observational study (ADVANCE‐ON). Other epidemiological analyses that were undertaken treated the trial as a cohort study, including using biomarkers from the blood samples taken from ADVANCE subjects as risk exposures. Results: More than 50 publications have reported epidemiological results from ADVANCE. The main results from ADVANCE‐ON suggested attenuated benefits of ADVANCE's blood pressure lowering treatment on all‐cause and cardiovascular death, but no such long‐term benefits for intensive glucose control, although this did give persistent benefit for end‐stage renal disease. The other epidemiological studies found, amongst other things, strong effects of NT‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin T on macrovascular events, microvascular events and all‐cause death. Conclusions: Embedding post‐randomization and epidemiological analyses into clinical trials is worthwhile and can be highly productive in advancing scientific knowledge. [ABSTRACT FROM AUTHOR]

To assess the effects of intensive glucose control on the risk of major clinical outcomes according to estimated glomerular filtration rate (eGFR) levels in people with type 2 diabetes. Of 11 140 ADVANCE trial participants, 11 096 with baseline eGFR measurements were included, and classified into three eGFR groups: ≥90 mL/min/1.73 m2; 60 to 89 mL/min/1.73 m2; and < 60 mL/min/1.73 m2. Relative risk reduction of randomized intensive glucose control with regard to the composite outcome of major macro‐ and microvascular events, all‐cause death and cardiovascular death did not significantly vary by eGFR level (P for heterogeneity ≥0.49). The risk of severe hypoglycaemia increased with intensive glucose control; however, this risk did not vary across eGFR groups (P for heterogeneity = 0.83). The risk–benefit profile of intensive glucose control in patients with type 2 diabetes and impaired kidney function appears similar to that observed in those with preserved kidney function. [ABSTRACT FROM AUTHOR]

Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA‐REG OUTCOME, CANVAS Program, DECLARE TIMI‐58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction ≥.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction ≥.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men. [ABSTRACT FROM AUTHOR]

Aims: To evaluate 1,5‐anhydroglucitol (1,5‐AG) according to clinical outcomes and assess the effects of glucose‐ and blood pressure‐lowering interventions on change in 1,5‐AG levels in people with type 2 diabetes. Methods: We measured 1,5‐AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1‐year follow‐up visit in the ADVANCE trial. We examined baseline 1,5‐AG [< 39.7, 39.7‐66.2, ≥ 66.2 μmol/L (<6, 6‐10, ≥10 μg/mL)] and microvascular and macrovascular events and mortality using Cox regression models during 5 years of follow‐up. Using an intention‐to‐treat approach, we examined 1‐year change in 1,5‐AG (mean and percent) in response to the glucose‐ and blood pressure‐lowering interventions in the subsample. Results: Low 1,5‐AG level [<39.7 μmol/L vs ≥ 66.2 μmol/L (<6 μg/mL vs ≥10 μg/mL)] was associated with microvascular events (hazard ratio 1.28, 95% confidence interval 1.03‐1.60) after adjustment for risk factors and baseline glycated haemoglobin (HbA1c); however, the associations for macrovascular events and mortality were not independent of HbA1c. The glucose‐lowering intervention was associated with a significant 1‐year increase in 1,5‐AG (vs standard control) of 6.69 μmol/L (SE 2.52) [1.01 μg/mL (SE 0.38)], corresponding to an 8.26% (SE 0.10%) increase from baseline. We also observed an increase in 1,5‐AG of similar magnitude in response to the blood pressure intervention independent of the glucose‐lowering effect. Conclusions: Our results suggest that 1,5‐AG is a marker of risk in adults with type 2 diabetes, but only for microvascular events independently of HbA1c. We found that 1,5‐AG was improved (increased) in response to an intensive glucose‐lowering intervention, although the independent effect of the blood pressure‐lowering intervention on 1,5‐AG suggests potential non‐glycaemic influences. [ABSTRACT FROM AUTHOR]

Aims: Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. Methods: WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE‐ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. Results: Median follow‐up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11‐1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut‐points, the equivalent WHtR cut‐points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. Conclusions: In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article I Sex differences in risk factors for cognitive decline and dementia, including death as a competing risk, in individuals with diabetes: Results from the ADVANCE trial i by Jessica Gong et al., https://doi.org/10.1111/dom.14391. [Extracted from the article]