Publications by authors named "Peter Rossing"

395 Publications

Cardiovascular autonomic neuropathy and the impact on progression of diabetic kidney disease in type 1 diabetes.

BMJ Open Diabetes Res Care 2021 Oct;9(1)

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Introduction: We investigated the association between cardiovascular autonomic neuropathy (CAN) and decline in kidney function in type 1 diabetes.

Research Design And Methods: We included 329 persons with type 1 diabetes. CAN was assessed by cardiovascular reflex tests (CARTs): heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva maneuvre. Two or more pathological CARTs defined CAN diagnosis. Outcomes were yearly change in albuminuria or yearly change in estimated glomerular filtration rate (eGFR). An endpoint of eGFR decline >30%, development of end-stage kidney disease (ESKD) or death was examined.Associations were assessed by linear and Cox regression.

Results: Participants were aged 55.2 (9.4) years, 52% were male, with a diabetes duration of 40.1 (8.9) years, HbA of 7.9% (62.5 mmol/mol), eGFR 77.9 (27.7) mL/min/1.73 m, urinary albumin excretion rate of 14.5 (7-58) mg/24 hours, and 31% were diagnosed with CAN.CAN was associated with a 7.8% higher albuminuria increase per year (95% CI: 0.50% to 15.63%, p=0.036) versus no CAN. The endpoint of ESKD, all-cause mortality and ≥30% decline in eGFR was associated with CAN (HR=2.497, p=0.0254).

Conclusion: CAN and sympathetic dysfunction were associated with increase in albuminuria in individuals with type 1 diabetes suggesting its role as a potential marker of diabetic kidney disease progression.
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http://dx.doi.org/10.1136/bmjdrc-2021-002289DOI Listing
October 2021

Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.

Lancet Diabetes Endocrinol 2021 Oct 4. Epub 2021 Oct 4.

Study Design and Biostatistics Center, University of Utah Health Sciences, Salt Lake City, UT, USA.

Background: Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)-ie, the eGFR slope.

Methods: DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73m. Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete.

Findings: Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8-2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m per year [0·73 to 1·85]; p=0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m per year (-0·10 to 1·03; p=0·040). The total eGFR slope was steeper in patients with higher baseline HbA and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA and UACR.

Interpretation: Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA, and higher UACR.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S2213-8587(21)00242-4DOI Listing
October 2021

Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.

Lancet Diabetes Endocrinol 2021 Oct 4. Epub 2021 Oct 4.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands; The George Institute for Global Health, Sydney, NSW, Australia. Electronic address:

Background: Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial.

Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m and 75 mL/min per 1·73 m and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150.

Findings: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (p<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056).

Interpretation: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S2213-8587(21)00243-6DOI Listing
October 2021

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: A subgroup analysis from the FIDELIO-DKD trial.

Diabetes Obes Metab 2021 Sep 28. Epub 2021 Sep 28.

Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA.

Aims: Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone.

Materials And Methods: Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25-<75 ml/min per 1.73 m receiving optimized renin-angiotensin system blockade were randomized to finerenone or placebo.

Results: Of the 5674 patients analysed, overall, 394 (6.9%) received GLP-1RAs at baseline. A reduction in UACR with finerenone was observed with or without baseline GLP-1RA use; ratio of least-squares means 0.63 (95% confidence interval 0.56, 0.70) with GLP-1RA use and 0.69 (95% confidence interval 0.67, 0.72) without GLP-1RA use (p value for interaction .20). Finerenone also significantly reduced the primary kidney (time to kidney failure, sustained decrease in estimated glomerular filtration rate ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) versus placebo, with no clear difference because of GLP-1RA use at baseline (p value for interaction .15 and .51 respectively) or any time during the trial. The safety profile of finerenone was similar between subgroups.

Conclusions: This exploratory subgroup analysis suggests that finerenone reduces UACR in patients with or without GLP-1RA use at baseline, and the effects on kidney and CV outcomes are consistent irrespective of GLP-1RA use.
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http://dx.doi.org/10.1111/dom.14558DOI Listing
September 2021

A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function.

Kidney Int 2021 Sep 22. Epub 2021 Sep 22.

The George Institute for Global Health, Sydney, Australia; Department of Renal Medicine, University College London, London, UK.

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function.
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http://dx.doi.org/10.1016/j.kint.2021.09.005DOI Listing
September 2021

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

N Engl J Med 2021 Sep 23. Epub 2021 Sep 23.

From the Division of Nephrology (L.A.I., S.J.C., A.S.L.) and the Institute for Clinical Research and Health Policy Studies (H.T.), Tufts Medical Center, Tufts Clinical and Translational Science Institute, Tufts University (H.T.), the Section on Genetics and Epidemiology, Joslin Diabetes Center (A.D.), and the Department of Medicine, Harvard Medical School (A.D.) - all in Boston; the Renal-Electrolyte and Hypertension Division, Perelman School of Medicine (N.D.E.), and the Departments of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics (W.Y.), University of Pennsylvania, Philadelphia; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions (J.C., D.W., Y.S., M.E.G., E.S., S.H.B.), the Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine (D.C.C., M.E.G.), and the Department of Medicine, Division of Nephrology, University of Maryland School of Medicine (R.K.) - all in Baltimore; the Kidney Health Research Collaborative, San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco (M.M.E., M.G.S.), the Division of Nephrology, Department of Medicine, San Francisco VA Health Care System and University of California, San Francisco (M.M.E.), and the Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital and University of California, San Francisco (N.R.P.) - all in San Francisco; the Clinical Trial Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (M.F.); the Division of Biostatistics, Department of Population Health Sciences, University of Utah Health, Salt Lake City (T.G.); the Department of Clinical Chemistry and Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden (A.G.); the Faculty of Medicine, University of Iceland, Reykjavik, and the Icelandic Heart Association, Kopavogur - both in Iceland (V.G.); the Departments of Medicine and Epidemiology, University of Alabama at Birmingham, Birmingham (O.M.G.); the Departments of Laboratory Medicine and Pathology (A.B.K., J.C.S.), Pediatrics (M.M.), and Medicine (M.M.), University of Minnesota, Minneapolis, and the Division of Nephrology and Hypertension, Mayo Clinic, Rochester (A.D.R., V.E.T.) - all in Minnesota; the Faculty of Medical Sciences, University Medical Center Groningen, Groningen, the Netherlands (G.N.); the Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ (R.G.N.); the Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland (E.D.P.); Rush University Medical Center, Chicago (R.R.); and Steno Diabetes Center Copenhagen and the Department of Clinical Medicine, University of Copenhagen - both in Copenhagen (P.R.).

Background: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct.

Methods: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.

Results: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.

Conclusions: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
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http://dx.doi.org/10.1056/NEJMoa2102953DOI Listing
September 2021

Early Response in Albuminuria and Long-Term Kidney Protection during Treatment with an Endothelin Receptor Antagonist: A Prespecified Analysis from the SONAR Trial.

J Am Soc Nephrol 2021 Sep 22. Epub 2021 Sep 22.

D de Zeeuw, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands.

Whether early reduction in albuminuria with atrasentan treatment predicts its longterm kidney protective effect is unknown. To assess long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled diabetic patients with chronic kidney disease (stage 2-4) and a urinary albumin creatinine ratio (UACR) of 300 mg/g-5000 mg/g; participants were receiving maximum tolerated renin angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or end-stage kidney disease. UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata. Our findings do not support UACR response as a causal predictor of atrasentan's treatment effect. However, because of UACR's variable trajectory with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.
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http://dx.doi.org/10.1681/ASN.2021030391DOI Listing
September 2021

Effect of liraglutide on expression of inflammatory genes in type 2 diabetes.

Sci Rep 2021 Sep 17;11(1):18522. Epub 2021 Sep 17.

Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820, Gentofte, Denmark.

Anti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1β (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C-C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs' gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs.
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http://dx.doi.org/10.1038/s41598-021-97967-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448739PMC
September 2021

Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized controlled trial.

BMJ Open Diabetes Res Care 2021 09;9(1)

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Introduction: Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can reduce risk of cardiovascular disease (CVD) in persons living with type 2 diabetes, however the mechanisms explaining this cardiovascular benefit are still debated. We investigated changes in the plasma lipidome following treatment with the GLP-1 RA liraglutide.

Research Design And Methods: In a double-blind placebo-controlled trial, we randomized 102 persons with type 2 diabetes to liraglutide or placebo for 26 weeks. Fasting blood plasma was collected at baseline and at end-of-treatment. The lipidome was measured using liquid-chromatography-coupled mass-spectrometry as a secondary end point in the study. Treatment response of each lipid was tested with lipid-specific linear mixed-effect models comparing liraglutide with placebo. Bonferroni p<7.1e-03 was employed. The independence of the findings from clinical covariates was evaluated with adjustment for body mass index, HbA, fasting status, lipid-lowering treatment and change in lipid-lowering treatment during the trial.

Results: In total, 260 lipids were identified covering 11 lipid families. We observed significant decreases following liraglutide treatment compared with placebo in 21 lipids (p<7.1e-03) from the following lipid families: ceramides, hexocyl-ceramides, phosphatidylcholines, phosphatidylethanolamines and triglycerides. We confirmed these findings in adjusted models (p≤0.01). In the liraglutide-treated group, the individual lipids were reduced in the range of 14%-61% from baseline level, compared with 19% decrease to 27% increase from baseline level in the placebo group.

Conclusions: Compared with placebo, liraglutide treatment led to a significant downregulation in ceramides, phospholipids and triglycerides, which all are linked to higher risk of CVD. These findings were independent of relevant clinical covariates. Our findings are hypothesis generating and shed light on the biological mechanisms underlying the cardiovascular benefits observed with GLP-1 RAs in outcome studies, and further strengthen the evidence base for recommending GLP-1 RAs to prevent CVD in type 2 diabetes.

Trial Registration Number: NCT03449654.
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http://dx.doi.org/10.1136/bmjdrc-2021-002395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451300PMC
September 2021

A primer on metabolic memory: why existing diabesity treatments fail.

Clin Kidney J 2021 Mar 2;14(3):756-767. Epub 2020 Sep 2.

Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.

Despite massive government and private sector investments into prevention of cardiovascular disease, diabetes mellitus and obesity, efforts have largely failed, and the burden of cost remains in the treatment of downstream morbidity and mortality, with overall stagnating outcomes. A new paradigm shift in the approach to these patients may explain why existing treatment strategies fail, and offer new treatment targets. This review aims to provide a clinician-centred primer on metabolic memory, defined as the sum of irreversible genetic, epigenetic, cellular and tissue-level alterations that occur with long-time exposure to metabolic derangements.
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http://dx.doi.org/10.1093/ckj/sfaa143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422888PMC
March 2021

Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.

N Engl J Med 2021 Aug 28. Epub 2021 Aug 28.

From the Department of Medicine, University of Michigan School of Medicine, Ann Arbor (B.P.); National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Attikon University Hospital, Athens (G.F.); the Richard L. Roudebush Veterans Affairs Medical Center and Indiana University, Indianapolis (R.A.); the Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Center for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin (S.D.A.), and Research and Development, Cardiology and Nephrology Clinical Development (A.J.) and Statistics and Data Insights (P.S.), Bayer, Berlin, and Research and Development, Preclinical Research Cardiovascular (P.K.) and Clinical Development Operations (C.N.), Bayer, Wuppertal - all in Germany; the Department of Medicine, University of Chicago Medicine, Chicago (G.L.B.); Steno Diabetes Center Copenhagen, Gentofte, and the Department of Clinical Medicine, University of Copenhagen, Copenhagen - both in Denmark (P.R.); and the Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research i+12, Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, and the Faculty of Sport Sciences, European University of Madrid - all in Madrid (L.M.R.).

Background: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear.

Methods: In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events.

Results: A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%).

Conclusions: Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).
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http://dx.doi.org/10.1056/NEJMoa2110956DOI Listing
August 2021

Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure.

JACC Heart Fail 2021 Aug 5. Epub 2021 Aug 5.

The George Institute for Global Health, Sydney, Australia; Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Objectives: The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF).

Background: Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline.

Methods: A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified.

Results: HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF.

Conclusions: Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150).
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http://dx.doi.org/10.1016/j.jchf.2021.06.017DOI Listing
August 2021

Effect of Liraglutide on Vascular Inflammation Evaluated by [Cu]DOTATATE.

Diagnostics (Basel) 2021 Aug 8;11(8). Epub 2021 Aug 8.

Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, 1165 Copenhagen, Denmark.

Quantification of vascular inflammation before and after treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may help reveal mechanistic pathways underlying the cardiovascular benefits of these drugs. We assessed change in vascular inflammation in the carotid arteries over 26 weeks by copper-64-labeled [1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid]-D-Phe1, Tyr3-octreotate ([Cu]DOTATATE) PET in 30 participants included in a substudy of a double-blind trial where persons with type 2 diabetes (T2D) were randomized to liraglutide ( = 15) or placebo ( = 15) for 26 weeks. Mean age (SD) was 66.4 (7.2) years, HbA 56.4 (9.2) mmol/mol and BMI 28.9 (4.6) kg/m. Weight and HbA were significantly reduced by liraglutide vs. placebo ( ≤ 0.01). The [Cu]DOTATATE uptake (mean standardized uptake values) was significantly reduced in the liraglutide-treated group (-0.11 [95% confidence interval -0.19 to -0.03], = 0.01) and not changed significantly in the placebo group (-0.07 [-0.14 to 0.01], = 0.08). The mean difference between groups did not reach significance (-0.04 [-0.15 to 0.07], = 0.44). In conclusion, [Cu]DOTATATE uptake was reduced in persons with T2D treated with liraglutide. However, the reduction compared to placebo did not reach statistical significance, perhaps due to limited power. A reduction in vascular inflammation with liraglutide could help explain the cardiovascular protection observed with GLP-1 RAs in outcome studies but warrants further and larger studies.
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http://dx.doi.org/10.3390/diagnostics11081431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391433PMC
August 2021

Medical therapies for prevention of cardiovascular and renal events in patients with atrial fibrillation and diabetes mellitus.

Europace 2021 Aug 19. Epub 2021 Aug 19.

Cardiology Clinical Academic Group Molecular and Clinical Sciences Institute, St George's University of London, London, UK.

Atrial fibrillation (AF), type 2 diabetes mellitus (DM), and chronic kidney disease (CKD) are three global epidemics with significant effects on morbidity and mortality. Diabetes is a risk factor for AF, and a risk factor for thromboembolism, comorbidity, and mortality when AF is present. The pathophysiology of diabetes-related AF and interrelationships with cardiovascular events and renal events is not fully understood but is in part related to structural, electrical, electromechanical, and autonomic remodelling. The current practice guidelines offer limited recommendations on the management of patients with AF (or risk of AF) and diabetes with its own heterogeneity for the prevention of cardiovascular and renal events. This document discusses possible clinical approaches for these patients. In the last decade, there have been major improvements for the prevention of stroke in AF patients with direct oral anticoagulants, which are preferable to vitamin K antagonists for stroke prevention in DM. Because of the increased risk rate for several cardiovascular adverse events in diabetic patients, a similar relative risk reduction generally translates into greater absolute risk reduction in the diabetic population. Recent trials with non-insulin diabetes drugs using glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors showed a significant reduction for the risk of major adverse cardiovascular events in patients with type 2 DM. Sodium-glucose cotransporter-2 inhibitors also showed a large reduction in hospitalization for heart failure and renal events, which need to be more completely evaluated in patients with AF. Mechanisms, risks, and optimal management of AF patients with DM who have or are under risk of developing heart failure or CKD are also discussed in this document. The benefits of medical therapies for these patients still need to be put into perspective, and gaps in evidence on some of these issues are likely to be addressed in future years.
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http://dx.doi.org/10.1093/europace/euab184DOI Listing
August 2021

Liraglutide reduces cardiac adipose tissue in type 2 diabetes: A secondary analysis of the LIRAFLAME randomized placebo-controlled trial.

Diabetes Obes Metab 2021 Aug 13. Epub 2021 Aug 13.

Steno Diabetes Centre Copenhagen, Gentofte, Denmark.

Aim: To test the hypothesis that treatment with liraglutide can reduce cardiac adipose tissue.

Materials And Methods: LIRAFLAME is a randomized placebo-controlled, double-blind, parallel clinical study. Participants with type 2 diabetes were randomized to treatment with liraglutide 1.8 mg/d or placebo for 26 weeks. Computed tomography was performed at baseline and at end of treatment to evaluate the cardiac adipose tissue volume, quantified automatically. We report the results of a secondary endpoint evaluating changes in cardiac adipose tissue.

Results: A total of 102 participants were randomly assigned to liraglutide (n = 51) or placebo (n = 51). At baseline, the mean (SD) cardiac adipose tissue volume was comparable between the liraglutide and the placebo group (232.6 [112.8] vs. 227.0 [103.2] mL; P = 0.80). The mean change in body weight was -3.7 (-4.8, -2.6) kg in the liraglutide and -0.18 (-0.76, 0.40) kg in the placebo group. From baseline to end of treatment the mean cardiac adipose tissue change was -11.5 (95% confidence interval -17.6, -5.4) mL in the liraglutide (P < 0.001) and -0.01 (-5.3, 5.3) mL in the placebo (P = 1.00) groups. The reduction in cardiac adipose tissue was significantly greater in the liraglutide compared to the placebo group (mean difference -11.4 [-19.4, -3.3] mL; P = 0.006), but significance was lost after adjustment for changes in body mass index (P = 0.46).

Conclusion: Treatment with liraglutide for 26 weeks was associated with a reduction in cardiac adipose tissue compared to placebo. The reduction was not independent of weight loss, suggesting that this is not a drug-specific effect.
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http://dx.doi.org/10.1111/dom.14516DOI Listing
August 2021

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial.

EClinicalMedicine 2021 Jul 28;37:100895. Epub 2021 Jun 28.

Steno Diabetes Center Copenhagen, Denmark.

Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria.

Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed.

Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1·73m. The mean changes in renal cortical R* from baseline to six hours were for dapagliflozin -1·1 (SD 0·7) s and for placebo +1·3 (0·7) s, resulting in a difference between interventions of -2·3 s [95% CI -4·0 to -0·6];  = 0·012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events.

Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.
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http://dx.doi.org/10.1016/j.eclinm.2021.100895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343250PMC
July 2021

HbA1c and beyond.

Authors:
Peter Rossing

Nephrol Dial Transplant 2021 Aug 12. Epub 2021 Aug 12.

Steno Diabetes Center Copenhagen, Gentofte, DENMARK.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on Diabetes Management in Chronic Kidney Disease from 2020 comes at an opportune time when progress in diabetes technology and therapeutics offer new options to manage the large population of patients with diabetes and CKD at high risk of poor health outcomes. Management of hemoglobin A1c is important in diabetes but an enlarging base of evidence from large clinical trials have demonstrated important new treatments offering organ protection and not just glucose management, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. It is the ambition that the guideline can help to optimize the clinical care of people with diabetes and CKD by integrating new options with existing management strategies based on high quality evidence. Here the focus has been on comprehensive care of patients with diabetes and CKD, glycemic monitoring and targets, antihyperglycemic therapies in patients with diabetes and CKD, and new developments since the guideline was published offering new opportunities and a wider target population for the new interventions.
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http://dx.doi.org/10.1093/ndt/gfab243DOI Listing
August 2021

Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes: an IMIRHAPSODY Study.

Diabetes 2021 Aug 10. Epub 2021 Aug 10.

Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, CRC, Lund University, SUS, Malmö, Sweden.

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
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http://dx.doi.org/10.2337/db20-1281DOI Listing
August 2021

Endothelial glycocalyx and cardio-renal risk factors in type 1 diabetes.

PLoS One 2021 30;16(7):e0254859. Epub 2021 Jul 30.

Complication Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Background: Glycocalyx lines the inner surface of the capillary endothelium. Capillaroscopy enables visualization of the sublingual capillaries and measurement of the Perfused Boundary Region (PBR) as an estimate of the glycocalyx. Novel software enables assessment of the PBR estimated at a fixed high flow level (PBR-hf) and an overall microvascular assessment by the MicroVascular Health Score (MVHS). Damaged glycocalyx may represent microvascular damage in diabetes and assessment of its dimension might improve early cardio-renal risk stratification.

Aim: To assess the associations between PBR, PBR-hf and MVHS and cardio-renal risk factors in persons with type 1 diabetes (T1D); and to compare these dimensions in persons with T1D and controls.

Methods: Cross-sectional study including 161 persons with T1D stratified according to level of albuminuria and 50 healthy controls. The PBR, PBR-hf and MVHS were assessed by the GlycoCheck device (valid measurements were available in 136 (84.5%) with T1D and in all the controls). Higher PBR and PBR-hf indicate smaller glycocalyx width. Lower MVHS represents a worse microvascular health.

Results: There were no associations between PBR, PBR-hf or MVHS and the cardio-renal risk factors in persons with T1D, except for higher PBR-hf and lower MVHS in females (p = 0.01 for both). There was no difference in PBR, PBR-hf or MVHS in persons with normo-, micro- or macroalbuminuria. The PBR was higher (2.20±0.30 vs. 2.03±0.18μm; p<0.001) and MVHS lower (3.15±1.25 vs. 3.53±0.86μm; p = 0.02) in persons with T1D compared to controls (p≤0.02). After adjustment for cardio-renal risk factors the difference in PBR remained significant (p = 0.001).

Conclusions: The endothelial glycocalyx dimension was impaired in persons with T1D compared to controls. We found no association between the endothelial glycocalyx dimension and the level of albuminuria or cardio-renal risk factors among persons with T1D. The use of the GlycoCheck device in T1D may not contribute to cardio-renal risk stratification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323905PMC
July 2021

Faecal biomarkers in type 1 diabetes with and without diabetic nephropathy.

Sci Rep 2021 07 26;11(1):15208. Epub 2021 Jul 26.

Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820, Gentofte, Denmark.

Gastrointestinal dysbiosis is common among persons with type 1 diabetes (T1D), but its potential impact on diabetic nephropathy (DN) remains obscure. We examined whether faecal biomarkers, previously associated with low-grade gastrointestinal inflammation, differ between healthy controls and T1D subjects with and without DN. Faecal samples were analyzed for levels of calprotectin, intestinal alkaline phosphatase (IAP), short-chain fatty acids (SCFA) and immunoglobulins in subjects with T1D (n = 159) and healthy controls (NDC; n = 50). The subjects with T1D were stratified based on albuminuria: normoalbuminuria (< 30 mg/g; n = 49), microalbuminuria (30-299 mg/g; n = 50) and macroalbuminuria (≥ 300 mg/g; n = 60). aecal calprotectin, IAP and immunoglobulin levels did not differ between the T1D albuminuria groups. However, when subjects were stratified based on faecal calprotectin cut-off level (50 µg/g), macroalbuminuric T1D subjects exceeded the threshold more frequently than NDC (p = 0.02). Concentrations of faecal propionate and butyrate were lower in T1D subjects compared with NDC (p = 0.04 and p = 0.03, respectively). Among T1D subjects, levels of branched SCFA (BCFA) correlated positively with current albuminuria level (isobutyrate, p = 0.03; isovalerate, p = 0.005). In our study cohort, fatty acid metabolism seemed to be altered among T1D subjects and those with albuminuria compared to NDC. This may reflect gastrointestinal imbalances associated with T1D and renal complications.
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http://dx.doi.org/10.1038/s41598-021-94747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313679PMC
July 2021

Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.

J Am Heart Assoc 2021 08 19;10(15):e020418. Epub 2021 Jul 19.

Department of Endocrinology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark.

Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A by 0.76% (95% CI, 1.0-0.5; <0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; <0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.
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http://dx.doi.org/10.1161/JAHA.120.020418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475664PMC
August 2021

Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease.

J Am Soc Nephrol 2021 Sep 16;32(9):2352-2361. Epub 2021 Jul 16.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Background: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.

Methods: Adults with eGFR of 25-75 ml/min per 1.73 m and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.

Results: A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m per year in the dapagliflozin and placebo groups, respectively (=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.

Conclusions: Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.
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http://dx.doi.org/10.1681/ASN.2021020167DOI Listing
September 2021

Sodium-glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: Review of the current evidence.

Nephrology (Carlton) 2021 Jul 14. Epub 2021 Jul 14.

Steno Diabetes Center Copenhagen, Copenhagen Denmark and University of Copenhagen, Copenhagen, Denmark.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are promising drugs to treat chronic kidney disease patients with or without diabetes mellitus (DM). Besides improving glycemic control, SGLT2i are cardioprotective and kidney protective and decrease bodyweight, serum uric acid, blood pressure, albuminuria and glomerular hyperfiltration. These effects may benefit graft function and survival in kidney transplant (KT) patients. In this review, we evaluate data on the efficacy and safety of SGLT2i for KT patients with DM. Eleven studies with 214 diabetic KT patients treated with SGLT2i have been reported. SGLT2i lowered haemoglobin A1c and bodyweight. While glomerular filtration rate may be reduced in the short-term, it remained similar to baseline after 3-12 months. In two studies, blood pressure decreased and remained unchanged in the others. There were no significant changes in urine protein to creatinine ratio. Regarding safety, 23 patients had urinary tract infections, 2 patients had a genital yeast infection, one had acute kidney injury, and one had mild hypoglycaemia. No cases of ketoacidosis or acute rejection were reported. In conclusion, the limited experience so far suggests that SGLT2i are safe in KT patients with DM, decrease bodyweight and improve glycemic control. However, some of the benefits observed in larger studies in the non-KT population have yet to be demonstrated in KT recipients, including preservation of kidney function, reduction in blood pressure and decreased proteinuria.
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http://dx.doi.org/10.1111/nep.13941DOI Listing
July 2021

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 () with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

J Am Soc Nephrol 2021 Oct 14;32(10):2634-2651. Epub 2021 Jul 14.

Research Division, Joslin Diabetes Center, Boston, Massachusetts.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models.

Results: Protein coding variants in the hydroxysteroid 17- dehydrogenase 14 gene (), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (=4196; value=3.3 × 10). The gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies.

Conclusions: gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
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http://dx.doi.org/10.1681/ASN.2020101457DOI Listing
October 2021

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes.

Diabetes Care 2021 Sep 8;44(9):2098-2106. Epub 2021 Jul 8.

Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, MI

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D.

Research Design And Methods: In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform.

Results: At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 ( = 0.039). Observations were confirmed in the validation subset.

Conclusions: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D.
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http://dx.doi.org/10.2337/dc21-0737DOI Listing
September 2021

The Low-Expression Variant of Is Associated With Cardiovascular Disease in Type 1 Diabetes.

Diabetes 2021 Oct 9;70(10):2391-2401. Epub 2021 Jul 9.

Folkhälsan Research Center, Helsinki, Finland.

Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% ( = 0.04), CAD by 26% ( = 0.006), and CVD by 17% ( = 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.
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http://dx.doi.org/10.2337/db21-0056DOI Listing
October 2021

Successful glucose lowering therapy triumphs in heart failure.

Authors:
Peter Rossing

EClinicalMedicine 2021 Jul 26;37:100996. Epub 2021 Jun 26.

Steno Diabetes Center Copenhagen Gentofte 2820 Denmark.

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http://dx.doi.org/10.1016/j.eclinm.2021.100996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250160PMC
July 2021

Urinary peptidome and diabetic retinopathy in the DIRECT-Protect 1 and 2 trials.

Diabet Med 2021 Sep 18;38(9):e14634. Epub 2021 Jul 18.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Background: Given the association of diabetic retinopathy (DR) and kidney disease, we investigated the urinary peptidome to presence and deterioration of DR in a post hoc analysis of trials investigating the effect of candesartan on progression of DR in type 1 and type 2 diabetes, respectively.

Methods: Baseline urinary peptidomic analysis was performed on a random selection of 783 and 792 subjects in two randomized controlled trials, DIRECT-Protect 1 and 2, respectively. End points were two-step (RET2) and three-step (RET3) change in Early Treatment of Diabetic Retinopathy Study protocol (ETDRS) defined level. Peptide levels were correlated to baseline EDTRS level in a discovery set of 2/3 of the participants from DIRECT-Protect 1. The identified peptides were then validated cross-sectionally in the remaining 1/3 from DIRECT-Protect 1. Thereafter, peptides identified in the discovery set were assessed in the entire DIRECT-Protect 1 and 2 cohorts and significant peptides were tested longitudinally.

Results: Follow-up ranged 4.0-4.7 years. 24 peptides were associated with baseline DR in the discovery set. COL3A1 (seq: NTG~) and COL4A1 (seq: DGA~) were associated with baseline DR in the validation set (Rho: -.223, p < 0.001 and Rho: -.141, p = 0.024). Neither was significantly associated with end points. Assessing the 24 identified peptides in the entire cohorts, several collagen peptides were associated with baseline DR and end points; however, there was no overlap across diabetes types.

Conclusions: We identified several urinary peptides (mainly collagen) associated with the presence of DR, however they could not be conclusively associated with worsening of DR.
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September 2021

Effect of Liraglutide on Arterial Inflammation Assessed as [F]FDG Uptake in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial.

Circ Cardiovasc Imaging 2021 Jul 30;14(7):e012174. Epub 2021 Jun 30.

Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark (R.S.R., J.K.J., T.B., A.K.).

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 [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 [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], =0.53). Secondary analyses restricted to [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 (=0.052).

Conclusions: In this low to moderate risk population with type 2 diabetes, liraglutide did not change vascular inflammation assessed as [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.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300846PMC
July 2021
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