X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Cumulative Systolic Blood Pressure Load and Cardiovascular Risk in Patients With Diabetes.

BACKGROUND: Standard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time. OBJECTIVES: The purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes. METHODS: A post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models. RESULTS: Over a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes. CONCLUSIONS: Cumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286).

Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors.

BACKGROUND AND OBJECTIVES: Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to <5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (<3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median). RESULTS: During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00; P=0.04) compared with placebo. The magnitude of effects did not differ across subgroups defined by short-term changes in serum potassium during run-in (P for heterogeneity =0.66). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, major coronary events, major cerebrovascular events, and new or worsening nephropathy (P for heterogeneity ≥0.27). CONCLUSIONS: Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control.

AIMS/HYPOTHESIS: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. METHODS: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. RESULTS: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10-21 and p = 9.6 × 10-31, respectively) and a 4.4-fold (p = 6.8 × 10-33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. CONCLUSIONS/INTERPRETATION: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.

COMMD5 Inhibits Malignant Behavior of Renal Cancer Cells.

BACKGROUND/AIM: Copper metabolism MURR1 domain-containing 5 (COMMD5) is mainly expressed in renal tubules (RTs), where it facilitates re-differentiation of injured RTs. We reported that COMMD5 regulates the expression of epidermal growth factor receptor by participating in its endocytic membrane trafficking, thus inhibiting tumor growth. Here we aimed to determine the role of COMMD5 in malignant phenotypes of renal cell carcinoma (RCC). MATERIALS AND METHODS: The associations between COMMD5 levels in RTs adjacent to RCC tumors in patients and their clinicopathologic characteristics were evaluated, and the effects of COMMD5 on cancer stemness in RCC cells were investigated. RESULTS: Low COMMD5 levels in RTs correlated with high tumorigenesis and poor patient outcomes. COMMD5 overexpression in RCC cells reduced the proportion of cancer stem cell-like cells and their malignant phenotypes, including proliferation, invasion and sphere formation. Secreted COMMD5 from RT cells also reduced malignant phenotypes. CONCLUSION: COMMD5 might suppress malignant phenotypes of RCC, thus inhibiting tumor development and improving patient prognosis.

The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial.

OBJECTIVE: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

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.

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.

The comparative effects of intensive glucose lowering in diabetes patients aged below or above 65 years: Results from the ADVANCE trial.

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.

Variability in estimated glomerular filtration rate and the risk of major clinical outcomes in diabetes: Post hoc analysis from the ADVANCE trial.

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.

SARS-CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been identified as the entry receptor for coronaviruses into human cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Since hypertension (HT) is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and HT in interaction with specific pre-existing conditions known to be associated with COVID-19 severity. METHODS: Genetic analysis of ACE2 gene was conducted in French-Canadian (FC) and British populations. RESULTS: In FC individuals, the T allele of the single nucleotide polymorphism rs2074192 of ACE2 gene was a risk factor for HT in adult obese males [odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.06-1.83)] and even more so in obese males who smoked (OR = 1.67, CI: 1.24-2.55), but not in lean males, non-smoker males or females. The T allele was significantly associated with severity of HT and with earlier penetrance of HT in obese smoking males. Significant interaction between the T allele and obesity was present in both sexes. The association of ACE2 (rs233575) genotype with blood pressure was also seen in adolescents but the interaction with obesity was present only in females. Several variants in ACE2 gene were found to be associated with HT in obese, smoking males in British individuals of the UK Biobank. In addition, we observed more severe outcomes to COVID-19 in association with ACE2 risk alleles in obese, smoking males. CONCLUSIONS: This is the first report that ACE2 variants are associated with earlier penetrance and more severe HT and with more severe outcomes of COVID-19 in obese smoking males.

Economic Evaluation of a New Polygenic Risk Score to Predict Nephropathy in Adult Patients With Type 2 Diabetes.

OBJECTIVES: The current screening method for diabetic nephropathy (DN) is based on detection of albumin in the urine and decline of glomerular filtration rate. The latter usually occurs relatively late in the course of the disease. A polygenic risk score (PRS) was recently developed for early prediction of the risk for patients with type 2 diabetes (T2D) to develop DN. The aim of this study was to assess the economic impact of the implementation of the PRS for early prediction of DN in patients with T2D compared with usual screening methods in Canada. METHODS: A cost-utility analysis was developed using a Markov model. Health states include pre-end-stage renal disease (ESRD), ESRD and death. Model efficacy parameters were based on prediction of outcome data by polygenic risk testing of the genotyped participants in the Action in Diabetes and Vascular Disease PreterAx and DiamicronN Controlled Evaluation trial. Analyses were conducted from Canadian health-care and societal perspectives. Deterministic and probabilistic sensitivity analyses were conducted to assess results robustness. RESULTS: Over a lifetime horizon, the PRS was a dominant strategy, from both a health-care system and societal perspective. The PRS was less expensive and more efficacious in terms of quality-adjusted life-years compared with usual screening technics. Deterministic and probabilistic sensitivity analyses showed that results remained dominant in most simulations. CONCLUSIONS: This economic evaluation demonstrates that the PRS is a dominant option compared with usual screening methods for the prevention of DN in patients with T2D. Adoption of the PRS would reduce costs saving but would also help prevent ESRD and improve patients' quality of life.

Alternative kidney filtration markers and the risk of major macrovascular and microvascular events, and all-cause mortality in individuals with type 2 diabetes in the ADVANCE trial.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. METHODS: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), ß2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors. RESULTS: Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a >2-fold higher risk of all clinical outcomes. CONCLUSIONS: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted.

Sex-specific associations between cardiovascular risk factors and myocardial infarction in patients with type 2 diabetes: The ADVANCE-ON study.

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.

Plasma fatty acids and the risk of vascular disease and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE study.

AIMS/HYPOTHESIS: This biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes. METHODS: A case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of (median) follow-up, was undertaken as a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study (full details of the study design and primary endpoints of the ADVANCE trial and its case-cohort have been published previously). This current study considers new data: fatty acids measured from baseline plasma samples by proton NMR analysis. The fatty acids measured were n-3, docosahexaenoic acid (DHA), n-6, linoleic acid, and polyunsaturated, monounsaturated and saturated fatty acids. HRs were modelled per SD higher (percentage) fatty acid. C statistics and continuous net reclassification improvement were used to test the added value of fatty acids compared with traditional cardiovascular risk factors. RESULTS: After adjustment for traditional cardiovascular risk factors, an inverse association was observed for n-3 fatty acids and DHA with the risk of macrovascular events (HR [95% CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively, per 1 SD higher percentage), and for n-3 fatty acids with the risk of death (HR 0.91 [95% CI 0.84, 0.99] per 1 SD higher percentage). Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in the predictive ability of models when any fatty acid was added. CONCLUSIONS/INTERPRETATION: Plasma n-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, while n-3 fatty acids were also inversely associated with death. These results support the cardioprotective effects of n-3 fatty acids and DHA and further merit testing the role of high-dose supplementation with n-3 fatty acids in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00145925. Graphical abstract.

The Risks of Cardiovascular Disease and Mortality Following Weight Change in Adults with Diabetes: Results from ADVANCE.

CONTEXT: Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes. OBJECTIVE: To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes. DESIGN AND SETTING: The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit. RESULTS: Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication. CONCLUSIONS: In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes.

Environmental and genetic contributions to diabetes.

Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by persistent hyperglycemia. Its two most common forms are type 1 diabetes (T1D) and type 2 diabetes (T2D), for which genetic and environmental risk factors act in synergy. Because it occurs in children and involves infectious, autoimmune or toxic destruction of the insulin-secreting pancreatic beta-cells, type 1 diabetes has been called juvenile or insulin-deficient diabetes. In type 2, patients can still secrete some insulin but its effectiveness may be attenuated by 'insulin resistance.' There is also a group of rare forms of diabetes in the young which are inherited as monogenetic diseases. Whether one calls the underlying process 'genes vs. environment' or 'nature vs nurture', diabetes occurs at the interface of the two domains. Together with our genetic background we are born tabula rasa-a blank slate upon which the story of life, with all its environmental inputs will be written. There is one proviso: the influence of epigenetic inheritance must also be considered. Thus, in the creation of databases that include "big data" originating from genomic as well as exposome (defined as: the totality of environmental exposure from conception to death), a broad perspective is crucial as these factors act in concert in such chronic illnesses as diabetes that, for example, are likely to require adoption of an appropriate lifestyle change. Also, it is becoming increasingly evident that epigenetic factors can modulate the interplay between genes and environment. Consequently, throughout the life of an individual nature and nurture interact in a complex manner in the development of diabetes. This review addresses the question of the contribution of gene and environment and their interactions in the development of diabetes.

The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: the ADVANCE-ON study.

AIMS/HYPOTHESIS: Some studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear. METHODS: We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study's primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation. RESULTS: A total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min-1 (1.73 m)-2 (SD 17) and the median urinary albumin/creatinine ratio was 14 µg/mg (interquartile range 7-38). The mean eGFR slope was -0.63 ml min-1 (1.73 m)-2 year-1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, <-1.63 ml min-1 [1.73 m]-2 year-1) was significantly associated with the subsequent risk of the primary outcome (HR 1.30 [95% CI 1.17, 1.43]) compared with a stable change in eGFR (middle 50%, -1.63 to 0.33). An annual substantial increase in eGFR (highest 25%, >0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]). CONCLUSIONS/INTERPRETATION: Our study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality. TRIAL REGISTRY NUMBER: ClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286.

Combination of Changes in Estimated GFR and Albuminuria and the Risk of Major Clinical Outcomes.

BACKGROUND AND OBJECTIVES: Whether combining changes in eGFR and urine albumin-to-creatinine ratio (UACR) is more strongly associated with outcomes compared with either change alone is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 8766 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study. Changes in eGFR and UACR (baseline to 2 years) were defined as ≥40% decrease, minor change, and ≥40% increase. The primary outcome was the composite of major macrovascular (nonfatal or fatal myocardial infarction, nonfatal or fatal stroke, or cardiovascular death), major kidney events (requirement for kidney replacement therapy or kidney death), and all-cause mortality. RESULTS: Over a median of 7.7 years of follow-up, 2191 primary outcomes were recorded. Strong linear associations between eGFR and UACR changes and subsequent risk of the outcome were observed. For eGFR, the hazard ratios were 1.58 (95% confidence interval [95% CI], 1.27 to 1.95) for a decrease ≥40% and 0.82 for an increase ≥40% (95% CI, 0.64 to 1.04) compared with minor change. For UACR, the hazard ratios were 0.96 (95% CI, 0.85 to 1.07) for a decrease ≥40% and 1.32 (95% CI, 1.19 to 1.46) for ≥40% increase compared with minor change. Compared with dual minor changes, both an eGFR decrease ≥40% and a UACR increase ≥40% had 2.31 (95% CI, 1.67 to 3.18) times the risk of the outcome, with evidence of interaction between the two markers. CONCLUSIONS: Clinically meaningful decreases in eGFR and increases in UACR over 2 years, independently and in combination, were significantly associated with higher risk of major clinical outcomes.