Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

Economic development in most areas of the world has resulted in increased purchasing power and available per capita food. Supermarkets and a growing fast-food industry have transformed our dietary pattern. Ultra-processed food rich on sugars and saturated fat is now the major source of energy in most countries. The shift in food supply is considered a major driver of the obesity epidemic and the increasing prevalence of accompanying complications, such as type 2 diabetes, cardiovascular disease and cancer. However, the global shift might also have direct effects on the increase in type 2 diabetes, cardiovascular disease and cancer, independently of overweight and obesity. The shift in the food supply is a major driver of the obesity epidemic.

Background: The mechanism behind the cardiovascular protection observed with human GLP-1 RA (glucagon-like peptide-1 receptor agonists) in type 2 diabetes is unknown. We hypothesized that treatment with the GLP-1 RA liraglutide had a positive effect on vascular inflammation. Methods: LIRAFLAME (Effect of liraglutide on vascular inflammation in type-2 diabetes: A randomized, placebocontrolled, double-blind, parallel clinical PET/CT trial) was a double-blind, randomized controlled trial performed at a single university hospital clinic in Denmark. Patients with type 2 diabetes were via computer-generated randomization list assigned (1:1) liraglutide up to 1.8 mg or placebo once daily for 26 weeks. The primary end point was change in vascular inflammation over 26 weeks assessed by [ 18 F]-fluorodeoxyglucose positron emission tomography/computed tomography. Analyses were based on intention-to-treat. Key secondary outcomes included change in other indices of atherosclerosis. Results: Between October 26, 2017, and August 16, 2019, 147 patients were screened and 102 were randomly assigned to liraglutide (n=51) or placebo (n=51) and 99 (97%) completed the trial. Change in the [ 18 F]-fluorodeoxyglucose positron emission tomography measure of vascular inflammation (active-segment target-to-background ratio) did not differ between treatment groups: change from baseline to 26 weeks was −0.04 (95% CI, −0.17 to 0.08) in the liraglutide group compared with −0.09 (−0.19 to 0.01) in the placebo group (mean difference, 0.05 [95% CI, −0.11 to 0.21], P =0.53). Secondary analyses restricted to [ 18 F]-fluorodeoxyglucose positron emission tomography of the carotid arteries as well as other indices of atherosclerosis confirmed the primary result. We performed an explorative analysis of interaction between treatment group and history of cardiovascular disease ( P =0.052). Conclusions: In this low to moderate risk population with type 2 diabetes, liraglutide did not change vascular inflammation assessed as [ 18 F]-fluorodeoxyglucose uptake compared with placebo. An explorative analysis indicated a possible effect in persons with history of cardiovascular disease, in line with current guidelines where liraglutide is recommended to patients with history of cardiovascular disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03449654.

BackgroundTo evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease.Methods200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model’s improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale.ResultsHigher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality.ConclusionIn persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0569-8) contains supplementary material, which is available to authorized users.

Aims/hypothesis Abnormal gut microbiota and blood metabolome profiles have been reported both in children and adults with uncomplicated type 1 diabetes as well as in adults with type 1 diabetes and advanced stages of diabetic nephropathy. In this study we aimed to investigate the gut microbiota and a panel of targeted plasma metabolites in individuals with type 1 diabetes of long duration without and with different levels of albuminuria. Methods In a cross-sectional study we included 161 individuals with type 1 diabetes and 50 healthy control individuals. Individuals with type 1 diabetes were categorised into three groups according to historically measured albuminuria: (1) normoalbuminuria (<3.39 mg/mmol); (2) microalbuminuria (3.39-33.79 mg/mmol); and (3) macroalbuminuria (≥33.90 mg/ mmol). From faecal samples, the gut microbiota composition at genus level was characterised by 16S rRNA gene amplicon sequencing and in plasma a targeted profile of 31 metabolites was analysed with ultra HPLC coupled to MS/MS. Results Study participants were aged 60 ± 11 years (mean ± SD) and 42% were women. The individuals with type 1 diabetes had had diabetes for a mean of 42 ± 15 years and had an eGFR of 75 ± 25 ml min −1 (1.73 m) −2 . Measures of the gut microbial beta diversity differed significantly between healthy controls and individuals with type 1 diabetes, either with micro-or macroalbuminuria. Taxonomic analyses showed that 79 of 324 genera differed in relative abundance between individuals with type 1 diabetes and healthy controls and ten genera differed significantly among the three albuminuria groups with type 1 diabetes. For the measured plasma metabolites, 11 of 31 metabolites differed significantly between individuals with type 1 diabetes and healthy controls. When individuals with type 1 diabetes were stratified by the level of albuminuria, individuals with macroalbuminuria had higher plasma concentrations of indoxyl sulphate and L-citrulline than those with normo-or microalbuminuria and higher plasma levels of homocitrulline and L-kynurenine compared with individuals with normoalbuminuria. Whereas plasma concentrations of tryptophan were lower in individuals with macroalbuminuria compared with those with normoalbuminuria. Conclusions/interpretation We demonstrate that individuals with type 1 diabetes of long duration are characterised by aberrant profiles of gut microbiota and plasma metabolites. Moreover, individuals with type 1 diabetes with initial stages of diabetic nephropathy show different gut microbiota and plasma metabolite profiles depending on the level of albuminuria.