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Background: This post-hoc study investigated whether biomarkers reflecting extracellular matrix (ECM) turnover predicted cardiovascular disease (CVD), mortality, and progression of diabetic kidney disease (DKD) in individuals with type 2 diabetes (T2D) and microalbuminuria., Methods: Serum levels of specific ECM turnover biomarkers were assessed in 192 participants with T2D and microalbuminuria from an observational study conducted at Steno Diabetes Center Copenhagen from 2007 to 2008. Endpoints included CVD events, mortality, and DKD progression, defined as decline in estimated glomerular filtration rate (eGFR) of >30 %., Results: Participants had a mean age of 59 years, with 75 % males. Over a median follow-up of 4.9 to 6.3 years, the study recorded 38 CVD events, 24 deaths, and 40 DKD events. Elevated levels of a degradation fragment of collagen type I (C1M) were associated with an increased risk of >30 % eGFR decline, although this association was not independent of other risk factors. No significant associations were found between other ECM turnover biomarkers and DKD progression, mortality, or CVD risk., Conclusion: Elevated C1M levels were linked to DKD progression in individuals with T2D and microalbuminuria, but not independently of other risk factors. None of the ECM turnover biomarkers were associated with CVD or mortality., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ALM, DGKR, FG, and MAK are employees of Nordic Bioscience. Nordic Bioscience is a privately owned, small- to medium-sized enterprise, partly focused on the development of biomarkers. None of the authors received fees, bonuses, or other benefits for the work regarding this article. DGKR, FG, and MAK holds stocks in Nordic Bioscience. Outside this work, BJvS is employed by Novo Nordisk, and PR has received institutional grants from Bayer, Novo Nordisk and AstraZeneca and has acted as consultant for Novo Nordisk, Bayer, Astellas, Boehringer Ingelheim, AstraZeneca, Gilead, Merk, Mundipharma, and Sanofi (honoraria to institution). The results presented in this paper have not been published previously in whole or part, except in abstract format., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Lipoprotein(a)(Lp(a)) has emerged as an independent risk marker for cardiovascular disease (CVD) in the general population and among persons with existing CVD. We investigated associations between serum Lp(a)concentrations and renal function decline, incident CVD and all-cause mortality in individuals with type 2 diabetes (T2D) and microalbuminuria., Methods: Prospective study including 198 individuals with T2D, microalbuminuria and no CVD. Yearly p-creatinine was measured after baseline in 176 of the participants. The renal endpoint was defined as decline in eGFR of >30% from baseline. CVD events and mortality were tracked from national registries. Cox regression analyses were applied both unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA 1c , creatinine and urinary albumin creatinine ratio (UAER))., Results: Baseline mean (SD) age was 59 (9)years, eGFR 89 (17) mL/min/1.73 m 2 , 77% were male, and median [IQR] UAER was 103 [38-242] mg/24-h. Median Lp(a)was 8.04 [3.42-32.3] mg/dL. Median follow-up was 6.1 years; 38 CVD events, 26 deaths and 43 renal events were recorded. For each doubling of baseline Lp(a), the following hazard ratios (95% confidence intervals) were found before and after adjustment respectively: 0.98 (0.84-1.15) and 1.01 (0.87-1.18) for decline in eGFR > 30%, 0.96 (0.81-1.13) and 0.99 (0.82-1.18) for CVD events, 1.04 (0.85-1.27) and 1.06 (0.87-1.30) for all-cause mortality., Conclusions: In this cohort of individuals with T2D and microalbuminuria, the baseline concentration of Lp(a)was not a risk marker for renal function decline, CVD events or all-cause mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Weight loss-induced serum creatinine reduction may increase creatinine-based estimated glomerular filtration rate (eGFR) producing incorrect estimates of kidney function. We investigated whether weight changes in the SCALE program with liraglutide 3.0mg were associated with changes in serum creatinine., Methods: Post hoc analysis of two 56-week, randomized, double-blind trials: SCALE Obesity and Prediabetes (n=3731, without type 2 diabetes [T2D], randomized [2:1] to liraglutide 3.0mg [n=2487] or placebo [n=1244]); SCALE Diabetes (n=846 with T2D, randomized [2:1:1] to liraglutide 3.0mg [n=423], 1.8mg [n=211, excluded from this analysis] or placebo [n=212]). NCT01272219/NCT01272232., Results: In SCALE Obesity and Prediabetes, mean (±SD) weight loss (baseline to week 56) with liraglutide was 8.0±6.7% (2.6±6.9% with placebo); baseline creatinine with liraglutide was 76±15μmol/L and 74±15μmol/L after 56weeks (similar across treatment groups). In SCALE Diabetes, weight loss with liraglutide was 5.9±5.5% (2.0±4.3% with placebo); baseline creatinine was 79±19μmol/L (77±16μmol/L, placebo) and 79±20μmol/L after 56weeks (76±15μmol/L, placebo). No association between changes in weight and changes in serum creatinine was observed (P≥0.05, both trials, all tests)., Conclusions: Moderate gradual body weight reductions observed in the SCALE program were not associated with changes in serum creatinine., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Management of diabetic nephropathy includes reduction of albuminuria, blood pressure and weight. The GLP-1 receptor agonist liraglutide may possess these pleiotropic effects in addition to the glucose lowering effect. We aimed to elucidate the individual liraglutide treatment response by determining if high responders (highest reduction) in each risk factor also had high response in other renal risk factors (cross-dependency)., Methods: Open-label study: 31 type 2 diabetics treated with liraglutide for 7weeks. After 3weeks washout 23 re-started treatment and were followed for 1year. HbA 1c , weight, systolic blood pressure (SBP), urinary albumin excretion rate (UAER) and mGFR ( 51 Cr-EDTA) were evaluated. Changes in high (Q4) vs. low responders (Q1-Q3) were compared for each renal risk factor. The effects of treatment/off treatment/re-treatment (off-on/off-on effect) were evaluated to account for random effects., Results: After 7weeks HbA 1c was reduced 6(95% CI: 3;9)mmol/mol, weight 2.5(1.8;3.2)kg, SBP 4(-1;9)mmHg, UAER 30(12;44)% and mGFR 11(7;14)ml/min per 1.73m 2 . mGFR high responders had a significant reduction in weight compared to low responders (4.3 vs. 1.9kg; p=0.002). SBP high responders had a tendency of a higher reduction in UAER compared to low responders (47 vs. 23%, p=0.14). No cross-dependency was observed in any of the other renal risk factors (p≥0.16). Treatment response did not differ after 7weeks and 1year (p≥0.12)., Conclusions/interpretation: Liraglutide possesses pleiotropic effects on renal risk factors. On patient level, effect on the individual risk factor cannot be anticipated based on response in other risk factors. Response when re-starting treatment did not differ, indicating that our primary findings were not random., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Aim: The bone-related peptide osteoprotegerin has been linked to vascular calcification and peripheral vascular disease. We investigated the association between osteoprotegerin and development of foot complications in persons with type 1 diabetes., Materials and Methods: Prospective observational study of 573 persons with type 1 diabetes, 225 women; age [mean±SD] 42.3±10.3years. Plasma osteoprotegerin was measured by ELISA., Results: Median (IQR) osteoprotegerin was 2.80(2.35-3.63)μg/L and follow-up time (median (range)) was 12.7(0.1-15.6)years. Endpoints included: new foot ulceration (n=153), Charcot foot (n=14), vascular surgery/amputation (n=53), loss of foot pulse (n=57), and peripheral neuropathy (n=99). In unadjusted analyses, higher osteoprotegerin was associated with development of all endpoints (p≤0.026). Higher osteoprotegerin remained associated with development of foot ulcer, and the combination of vascular surgery/amputation, loss of foot pulse and neuropathy (p≤0.001) in a sex and age adjusted model. After further adjustment (nephropathy status, smoking, HbA 1c , systolic blood pressure, serum cholesterol, high sensitivity C-reactive protein, eGFR, and presence of neuropathy and/or claudication and/or foot ulcer at baseline), higher osteoprotegerin remained associated with development of foot ulcer (HR (95% CI) per doubling: 1.75 (1.04-2.97); p=0.037)., Conclusion: Higher osteoprotegerin levels were associated with development of foot ulcer, even after comprehensive adjustment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known coronary artery disease (CAD)., Methods: Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-ɑ, sICAM-1, sICAM-3, hsCRP, SAA, IL-1β, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at baseline. Adjustment included traditional CVD risk factors, and full adjustment additionally NT-proBNP and CAC. The "SQRT method" assessed CAC progression after 5.8years, and cut-point was an annualised difference >2.5., Results: Occurrence of CVD (n=40) and all-cause mortality (n=26) was traced after 6.1years. In adjusted and fully adjusted Cox models, TNF-ɑ was a determinant of CVD and all-cause mortality (p≤0.007). Further, in adjusted and fully adjusted logistic regression, TNF-ɑ was related to CAC progression (p≤0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with both endpoints (p≤0.046), IL-1β with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p≤0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p≤0.008)., Conclusions: In patients with T2D and microalbuminuria without known CAD and receiving multifactorial treatment, biomarkers of inflammation and endothelial dysfunction were independently associated with CVD, all-cause mortality and CAC progression. Especially TNF-ɑ was a robust determinant, even after adjusting for NT-proBNP and CAC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Estimation of kidney function (eGFR) is essential in monitoring of patients with kidney disease. Estimates of kidney function based on serum creatinine are derived from cross-sectional studies. If body weight (BW) changes, this might affect creatinine and eGFR. The Cockcroft-Gault (CG) equation includes creatinine and BW, whereas the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations only include creatinine., Methods: Data were pooled from the six LEAD (Liraglutide Effect and Action in Diabetes) trials and the LIRA-DPP4 trial. The trials were conducted in patients with type 2 diabetes and of 26weeks duration. We investigated changes in eGFR for patients treated with liraglutide, and for patients treated with glucose-lowering medications with less weight-reducing effects (insulin glargine, glimepiride, exenatide and rosiglitazone)., Results: We included 5100 patients (liraglutide n=3173, comparator n=1927). Mean (SD) CKD-EPI eGFR was 81.2 (20.6) ml/min/1.73m(2) for liraglutide and 81.6 (20.3) ml/min/1.73m(2) for comparator. For liraglutide, BW changed -1.9 (95% CI (-2.0; -1.8)) kg, for comparator BW changed 0.2 (95% CI (0.03; 0.3)) kg. Using regression modelling, a 10% BW decrease yielded no change in creatinine, MDRD eGFR or CKD-EPI eGFR for both liraglutide and comparator, but was associated with a 10.2% (-11.3%; -9.1%) decrease in CG eGFR for liraglutide, and a 10.6% (-12.0%; -9.1%) decrease for comparator., Conclusions: A liraglutide-induced weight reduction of 1.9kg was not associated with change in creatinine. Accordingly, there was no change in weight-independent estimates of GFR, whereas weight-dependent estimates were changed. The MDRD and CKD-EPI equations can be used in patients experiencing pharmaceutically induced weight reductions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to investigate the long-term effect on kidney function., Methods: We included 30 patients in a one-year extension study, all initially treated with liraglutide for seven weeks. During follow-up 23 were treated with liraglutide and seven untreated. Primary outcome was change in GFR ((51)Cr-EDTA plasma clearance)., Results: Patients were 61.5 (10.0) years and HbA(1c) 60.1 (13.8) mmol/mol. Baseline GFR was 100.6 (24.9) mL/min/1.73 m(2) and was reduced by 11 (95% CI: 6.6-15.7, p < 0.001) mL/min/1.73 m(2), independent of change in 24-h systolic blood pressure (SBP), weight, UAER or HbA(1c) (p≥0.33). Geometric mean (IQR) of UAER was 25.5 (9.9-50.9) mg/d and was reduced by 27 (95% CI: 5-44; p = 0.020)%, and 24-h SBP was reduced by 8.2 (p = 0.048) mmHg. No changes occurred in untreated patients., Conclusions: Long-term treatment with liraglutide was associated with a reduction in measured GFR similar to the effect during short-term treatment, suggesting a metabolic or haemodynamic reversible effect and not structural changes. Moreover, UAER and 24-h SBP were reduced., Trial Registration: ClinicalTrials.gov identifier: NCT01499108., (Copyright © 2015 Elsevier Inc. All rights reserved.)