The Effectiveness of Digital Health Lifestyle Interventions on People With Prediabetes: Protocol for a Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: There has been an increasing interest in the use of digital health lifestyle interventions for people with prediabetes, as these interventions may offer a scalable approach to preventing type 2 diabetes. Previous systematic reviews on digital health lifestyle interventions for people with prediabetes had limitations, such as a narrow focus on certain types of interventions, a lack of statistical pooling, and no broader subgroup analysis of intervention characteristics. The identified limitations observed in previous systematic reviews substantiate the necessity of conducting a comprehensive review to address these gaps within the field. This will enable a comprehensive understanding of the effectiveness of digital health lifestyle interventions for people with prediabetes. OBJECTIVE: The objective of this systematic review, meta-analysis, and meta-regression is to systematically investigate the effectiveness of digital health lifestyle interventions on prediabetes-related outcomes in comparison with any comparator without a digital component among adults with prediabetes. METHODS: This systematic review will include randomized controlled trials that investigate the effectiveness of digital health lifestyle interventions on adults (aged 18 years or older) with prediabetes and compare the digital interventions with nondigital interventions. The primary outcome will be change in body weight (kg). Secondary outcomes include, among others, change in glycemic status, markers of cardiometabolic health, feasibility outcomes, and incidence of type 2 diabetes. Embase, PubMed, CINAHL, and CENTRAL (Cochrane Central Register of Controlled Trials) will be systematically searched. The data items to be extracted include study characteristics, participant characteristics, intervention characteristics, and relevant outcomes. To estimate the overall effect size, a meta-analysis will be conducted using the mean difference. Additionally, if feasible, meta-regression on study, intervention, and participant characteristics will be performed. The Cochrane risk of bias tool will be applied to assess study quality, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach will be used to assess the certainty of evidence. RESULTS: The results are projected to yield an overall estimate of the effectiveness of digital health lifestyle interventions on adults with prediabetes and elucidate the characteristics that contribute to their effectiveness. CONCLUSIONS: The insights gained from this study may help clarify the potential of digital health lifestyle interventions for people with prediabetes and guide the decision-making regarding future intervention components. TRIAL REGISTRATION: PROSPERO CRD42023426919; http://tinyurl.com/d3enrw9j. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50340.

Obesity-Related Kidney Disease: Current Understanding and Future Perspectives.

Obesity is a serious chronic disease and an independent risk factor for the new onset and progression of chronic kidney disease (CKD). CKD prevalence is expected to increase, at least partly due to the continuous rise in the prevalence of obesity. The concept of obesity-related kidney disease (OKD) has been introduced to describe the still incompletely understood interplay between obesity, CKD, and other cardiometabolic conditions, including risk factors for OKD and cardiovascular disease, such as diabetes and hypertension. Current therapeutics target obesity and CKD individually. Non-pharmacological interventions play a major part, but the efficacy and clinical applicability of lifestyle changes and metabolic surgery remain debatable, because the strategies do not benefit everyone, and it remains questionable whether lifestyle changes can be sustained in the long term. Pharmacological interventions, such as sodium-glucose co-transporter 2 inhibitors and the non-steroidal mineralocorticoid receptor antagonist finerenone, provide kidney protection but have limited or no impact on body weight. Medicines based on glucagon-like peptide-1 (GLP-1) induce clinically relevant weight loss and may also offer kidney benefits. An urgent medical need remains for investigations to better understand the intertwined pathophysiologies in OKD, paving the way for the best possible therapeutic strategies in this increasingly prevalent disease complex.

Ceramides are decreased after liraglutide treatment in people with type 2 diabetes: a post hoc analysis of two randomized clinical trials.

BACKGROUND: Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D). METHODS: This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses. RESULTS: In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction. CONCLUSIONS: It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties. TRIAL REGISTRATION: Clinicaltrial.gov identifier: NCT02545738 and NCT03449654.

Glucagon-like peptide-1 receptor agonists to expand the healthy lifespan: Current and future potentials.

To help ensure an expanded healthy lifespan for as many people as possible worldwide, there is a need to prevent or manage a number of prevalent chronic diseases directly and indirectly closely related to aging, including diabetes and obesity. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have proven beneficial in type 2 diabetes, are amongst the few medicines approved for weight management, and are also licensed for focused cardiovascular risk reduction. In addition, strong evidence suggests several other beneficial effects of the pleiotropic peptide hormone, including anti-inflammation. Consequently, GLP-1 RAs are now in advanced clinical development for the treatment of chronic kidney disease, broader cardiovascular risk reduction, metabolic liver disease and Alzheimer's disease. In sum, GLP-1 RAs are positioned as one of the pharmacotherapeutic options that can contribute to addressing the high unmet medical need characterising several prevalent aging-related diseases, potentially helping more people enjoy a prolonged healthy lifespan.

Marker for kidney fibrosis is associated with inflammation and deterioration of kidney function in people with type 2 diabetes and microalbuminuria.

BACKGROUND: Diabetic kidney disease is a major cause of morbidity and mortality. Dysregulated turnover of collagen type III is associated with development of kidney fibrosis. We investigated whether a degradation product of collagen type III (C3M) was a risk marker for progression of chronic kidney disease (CKD), occurrence of cardiovascular disease (CVD), and mortality during follow up in people with type 2 diabetes (T2D) and microalbuminuria. Moreover, we investigated whether C3M was correlated with markers of inflammation and endothelial dysfunction at baseline. METHODS: C3M was measured in serum (sC3M) and urine (uC3M) in 200 participants with T2D and microalbuminuria included in an observational, prospective study at Steno Diabetes Center Copenhagen in Denmark from 2007-2008. Baseline measurements included 12 markers of inflammation and endothelial dysfunction. The endpoints were CVD, mortality, and CKD progression (>30% decline in eGFR). RESULTS: Mean (SD) age was 59 (9) years, eGFR 90 (17) ml/min/1.73m2 and median (IQR) urine albumin excretion rate 102 (39-229) mg/24-h. At baseline all markers for inflammation were positively correlated with sC3M (p≤0.034). Some, but not all, markers for endothelial dysfunction were correlated with C3M. Median follow-up ranged from 4.9 to 6.3 years. Higher sC3M was associated with CKD progression (with mortality as competing risk) with a hazard ratio (per doubling) of 2.98 (95% CI: 1.41-6.26; p = 0.004) adjusted for traditional risk factors. uC3M was not associated with CKD progression. Neither sC3M or uC3M were associated with risk of CVD or mortality. CONCLUSIONS: Higher sC3M was a risk factor for chronic kidney disease progression and was correlated with markers of inflammation.

In vivo molecular imaging of cardiac angiogenesis in persons with and without type 2 diabetes: A cross-sectional 68 Ga-RGD-PET study.

AIMS: To assess cardiac angiogenesis in type 2 diabetes by positron emission tomography (PET) tracer [68 Ga]Ga-NODAGA-E[(cRGDyK)]2 (68 Ga-RGD) imaging. METHODS: Cross-sectional study including 20 persons with type 2 diabetes and 10 non-diabetic controls (CONs). Primary prespecified outcome was difference in cardiac angiogenesis (cardiac 68 Ga-RGD mean target-to-background ratio [TBRmean ]) between type 2 diabetes and CONs. Secondary outcome was to investigate associations between cardiac angiogenesis and kidney function and other risk factors. RESULTS: Participants with type 2 diabetes had a mean ± SD age of 61 ± 9 years, 30% were women, median (IQR) diabetes duration of 11 (6-19) years and 3 (15%) had a history of cardiovascular disease. The CONs had comparable age and sex distribution to the participants with type 2 diabetes, and none had a history of coronary artery disease. Myocardial flow reserve was lower in type 2 diabetes (2.7 ± 0.6) compared with CONs (3.4 ± 1.2) ( p  = 0.03) and coronary artery calcium score was higher (562 [142-905] vs. 1 [0-150] p  = 0.04). Cardiac 68 Ga-RGD TBRmean was similar in participants with type 2 diabetes (0.89 ± 0.09) and CONs (0.89 ± 0.10) ( p  = 0.92). Cardiac 68 Ga-RGD TBRmean was not associated with estimated glomerular filtration rate, urine albumin creatinine ratio, cardiovascular disease, coronary artery calcium score or baroreflex sensitivity, neither in pooled analyses nor in type 2 diabetes. CONCLUSIONS: Cardiac angiogenesis, evaluated with 68 Ga-RGD PET, was similar in type 2 diabetes and CONs. Cardiac angiogenesis was not associated with kidney function or other risk markers in pooled analyses or in analyses restricted to type 2 diabetes.

The potential of glucagon-like peptide-1 receptor agonists in heart failure.

Heart failure (HF) remains one of the cardiovascular diseases (CVDs) associated with a high unmet medical need due to high morbidity and mortality rates and lack of efficacious interventions. HF is closely related to cardiometabolic diseases such as diabetes, obesity and chronic kidney disease, and strategies that address most or all these intertwined conditions are desirable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for type 2 diabetes (T2D), and some are also indicated for reduction of the risk of atherosclerotic CVD in T2D and for weight management. As we summarise in this concise review, preliminary evidence suggests that the cardioprotective benefits of GLP-1 RAs may also extend to HF. The most robust clinical evidence arguably originates from the large cardiovascular outcomes trials (CVOTs) completed for most GLP-1 RAs, of which the latest showed a significant relative risk reduction (RRR) of 39% (HR) with once-weekly efpeglenatide on HF requiring hospitalisation, corroborating a meta-analysis which found a significant RRR across eight GLP-1 RA CVOTs of 11%. Further, although incompletely described, multiple studies are available to provide insights into the mechanistic underpinnings, which appear to be associated mostly with indirect cardioprotective benefits owing to the ability of GLP-1 RAs to address hyperglycaemia, and reduce body weight, and, amongst others, inflammation. In sum, current evidence positions GLP-1 RAs as a potential cardioprotective strategy in HF, with HF with preserved ejection fraction emerging as the clinically most relevant phenotype for the drug class, especially when occurring in people with obesity with and without diabetes.

The potential of GLP-1 receptor agonists in type 2 diabetes and chronic kidney disease: from randomised trials to clinical practice.

Chronic kidney disease (CKD) affects around 10% of the global population and is most often caused by diabetes. Diabetes with CKD (diabetic kidney disease, DKD) is a progressive condition that may cause kidney failure and which contributes significantly to the excess morbidity and mortality in these patients. DKD is treated with direct disease-targeting therapies like blockers of the renin-angiotensin system, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and non-steroidal mineralocorticoid receptor antagonists as well as indirect therapies impacting hyperglycaemia, dyslipidaemia, obesity and hypertension, which all together reduce disease progression. While no glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are currently indicated to improve kidney outcomes, accumulating evidence from cardiovascular outcomes trials (CVOTs) corroborates a kidney-protective effect in people with T2D and CKD, and GLP-1 RAs are now mentioned in international treatment guidelines for type 2 diabetes (T2D) with CKD. GLP-1 RAs are indicated to improve glycaemia in people with T2D; certain GLP-1 RAs are also approved for weight management and to reduce cardiovascular risk in T2D. Ongoing pivotal trials are assessing additional indications, including T2D with CKD. In this article, we review and discuss kidney outcomes from a multitude of completed clinical trials as well as real-world evidence and ongoing clinical trials.

Interleukin 6 in diabetes, chronic kidney disease, and cardiovascular disease: mechanisms and therapeutic perspectives.

INTRODUCTION: Diabetes, chronic kidney disease (CKD) and cardiovascular disease (CVD) are cardiometabolic diseases that remain amongst the leading causes of morbidity and premature mortality. Here, we review the current understanding of how anti-inflammatory intervention via inhibition of the pro-inflammatory but pleiotropic cytokine interleukin (IL) 6 may benefit patients with these or related diseases or complications. AREAS COVERED: Based on a PubMed literature search, this review integrates and contextualizes evidence regarding the clinical utility of anti-IL-6 intervention in the treatment of cardiometabolic diseases, as well as of the associated condition nonalcoholic hepatosteatosis. EXPERT OPINION: Evidence implicates the pro-inflammatory effects of IL-6 in the pathophysiology of diabetes, CKD and CVD. Thus, targeting the IL-6 pathway holds a therapeutic potential in these cardiometabolic disorders. However, because IL-6 has multiple homeostatic roles, antagonizing this cytokine may be associated with side effects, such as increased risk of infection as seen with other anti-inflammatory drugs. Additional studies are required to establish the benefit-risk profile of anti-IL-6 intervention in the cardiometabolic diseases, whilst also considering alternative interventions such as lifestyle changes. IL-6 is also elevated in NASH, but the clinical usefulness of targeting IL-6 in this hepatic disorder remains largely unexplored.

The importance of addressing multiple risk markers in type 2 diabetes: Results from the LEADER and SUSTAIN 6 trials.

AIMS: To investigate to what extent multiple risk marker improvements confer lower risk of cardiovascular and kidney complications in a contemporary type 2 diabetes population. MATERIALS AND METHODS: Post-hoc analysis of the LEADER (n = 8638; median follow-up 3.8 years) and SUSTAIN 6 (n = 3040; median follow-up 2.1 years) cardiovascular outcome trials. Participants were those with baseline and year-1 assessment of at least one of the parameters of interest; we pooled the liraglutide-/semaglutide- and placebo-treated groups and categorized them by number of risk markers with clinically relevant improvements after 1 year of study participation. We investigated risk of major adverse cardiovascular events (MACE), expanded MACE, cardiovascular death and nephropathy. Predefined clinically relevant changes: body weight loss ≥5%; reductions in: glycated haemoglobin ≥1%, systolic blood pressure ≥5 mmHg and low-density lipoprotein cholesterol ≥0.5 mmol/L; estimated glomerular filtration rate change ≥0 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio change ≥30% of baseline value. Cox regression analysed risk of outcomes adjusted for baseline risk marker levels and treatment group and stratified by trial. RESULTS: Participants with two, three, or four or more improved risk markers versus participants with no risk marker improvement had reduced risk of expanded MACE [hazard ratio (95% confidence interval) 0.80 (0.67-0.96); 0.80 (0.66-0.97); 0.82 (0.66-1.02)], cardiovascular death [0.66 (0.45-0.96), 0.67 (0.45-0.99), 0.60 (0.38-0.94)] and nephropathy [0.71 (0.52-0.97), 0.48 (0.34-0.68), 0.43 (0.29-0.65)]. CONCLUSIONS: In persons with type 2 diabetes, improvements in ≥2 risk markers conferred cardiovascular risk reduction versus none or one improved risk marker. The nephropathy risk decreased with improvement in more risk markers. These findings stress the importance of multifactorial interventions targeting all risk markers.

Liraglutide Lowers Palmitoleate Levels in Type 2 Diabetes. A Post Hoc Analysis of the LIRAFLAME Randomized Placebo-Controlled Trial.

Background: Liraglutide is a glucose-lowering medication used to treat type 2 diabetes and obesity. It is a GLP-1 receptor agonist with downstream metabolic changes beyond the incretin system, such as reducing the risk of cardiovascular complications. The understanding of these changes is critical for improving treatment outcomes. Herein, we present a post hoc experimental analysis using metabolomic phenotyping to discover molecular mecphanisms in response to liraglutide. Method: Plasma samples were obtained from The LiraFlame Study (ClinicalTrials.gov identifier: NCT03449654), a randomized double-blinded placebo-controlled clinical trial, including 102 participants with type 2 diabetes randomized to either liraglutide or placebo treatment for 26 weeks. Mass spectrometry-based metabolomics analyses were carried out on samples from baseline and the end of the trial. Metabolites (n=114) were categorized into pathways and linear mixed models were constructed to evaluate the association between changes in metabolites and liraglutide treatment. Results: We found the free fatty acid palmitoleate was significantly reduced in the liraglutide group compared to placebo (adjusted for multiple testing p-value = 0.04). The activity of stearoyl-CoA desaturase-1 (SCD1), the rate limiting enzyme for converting palmitate into palmitoleate, was found significantly downregulated by liraglutide treatment compared to placebo (p-value = 0.01). These metabolic changes have demonstrated to be linked to insulin sensitivity and cardiovascular health.

The Association Between Cardiovascular Autonomic Function and Changes in Kidney and Myocardial Function in Type 2 Diabetes and Healthy Controls.

Background: The mechanisms linking cardiovascular autonomic neuropathy, diabetic kidney disease and cardiovascular mortality in type 2 diabetes are widely unknown. We investigated the relationship between baseline cardiovascular autonomic function and changes in kidney and myocardial function over six years in patients with type 2 diabetes and healthy controls. Methods: Post-hoc analysis of a cohort study in 24 patients with type 2 diabetes and 18 healthy controls. Baseline determinants were cardiovascular autonomic reflex tests (heart rate response to: standing (30:15); deep breathing (E:I); and the Valsalva test) and time- and frequency-domain heart rate variability indices. Outcomes were changes in estimated glomerular filtration rate (eGFR), albuminuria, myocardial flow reserve (MFR) measured by cardiac 82Rb Positron emission tomography computed tomography (PET/CT), and coronary artery calcium score (CACS). Results: Mean age at inclusion was 61 ± 10 years and 36% were female. Mean follow up time was 6 ± 0 years. A lower response in heart rate to the Valsalva test (corresponding to weaker autonomic function) was associated with a larger decline in eGFR (p=0.04), but not significantly after adjustment for sex, baseline age, smoking status, systolic blood pressure, heart rate, HbA1c, body mass index and baseline eGFR (p=0.12). A higher baseline response in heart rate to standing (30:15) was associated with a larger decline in myocardial flow reserve in the unadjusted analysis (p=0.02) and after adjustment (p=0.02). A higher response in heart rate to the Valsalva maneuver was associated with a larger increase in CACS (p = 0.02), but the association became insignificant after adjustment (p = 0.16). Conclusion: A lower response in heart rate to the Valsalva test was associated with a larger decline in kidney function, indicating that autonomic dysfunction may predict future loss of kidney function. However, we did not find any association between lower values in cardiovascular autonomic function at baseline and a worsening in albuminuria, myocardial function, or atherosclerotic burden.

Current state of antigen-specific immunotherapy for type 1 diabetes.

PURPOSE OF REVIEW: Update on antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D) with focus on deoxyribonucleic acid (DNA)-induced immunization and the current obstacles to further research and clinical realization. RECENT FINDINGS: In T1D, immune system imbalances together with malfunctioning islet-specific processes cause autoreactive immune cells to destroy beta cells in the islets. ASIT may restore self-tolerance; however, the approach has yet to fully meet its promise and may require co-administration of antigen (preproinsulin) and suitable immune response modifiers. SUMMARY: A self-tolerant immune system may be regained using ASIT where T effector cells are repressed and/or T regulatory cells are induced. Administration of exogenous antigens has been safe in T1D. Conversely, adequate and lasting beta cell preservation has yet to be tested in sufficiently large clinical trials in suitable patients and may require targeting of multiple parts of the immunopathophysiology using combination therapies. DNA-based induction of native antigen expression to ensure important posttranscriptional modifications and presentation to the immune system together with tolerance-enhancing immune response modifiers (i.e., cytokines) may be more efficacious than exogenous antigens given alone. Progress is limited mainly by the scarcity of validated biomarkers to track the effects of ASIT in T1D.

The effect of liraglutide and sitagliptin on oxidative stress in persons with type 2 diabetes.

Glucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (- 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (- 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

Plasma trimethylamine N-oxide and its metabolic precursors and risk of mortality, cardiovascular and renal disease in individuals with type 2-diabetes and albuminuria.

AIMS: The trimethylamine N-oxide (TMAO) pathway is related to intestinal microbiota and has been associated to risk of cardiovascular disease (CVD). We investigated associations between four plasma metabolites in the TMAO pathway and risk of all-cause mortality, CVD and deterioration in renal function in individuals with type 2-diabetes (T2D) and albuminuria. MATERIALS AND METHODS: Plasma concentrations of TMAO, choline, carnitine, and betaine were measured by liquid chromatography-tandem mass spectrometry at baseline in 311 individuals with T2D and albuminuria. Information on all-cause mortality and fatal/non-fatal CVD during follow-up was obtained from registries. The association of each metabolite, and a weighted sum score of all four metabolites, with the endpoints were examined. Serum creatinine was measured at follow-up visits and the renal endpoint was defined as eGFR-decline of ≥30%. Associations were analysed using proportional hazards models adjusted for traditional risk factors. RESULTS: Baseline mean(SD) age was 57.2(8.2) years and 75% were males. Follow-up was up to 21.9 years (median (IQR) follow-up 6.8 (6.1-15.5) years for mortality and 6.5 (5.5-8.1) years for CVD events). The individual metabolites and the weighted sum score were not associated with all-cause mortality (n = 106) or CVD (n = 116) (adjusted p≥0.09). Higher choline, carnitine and the weighted sum score of the four metabolites were associated with higher risk of decline in eGFR (n = 106) (adjusted p = 0.001, p = 0.03 and p<0.001, respectively). CONCLUSIONS: In individuals with T2D and albuminuria, higher choline, carnitine and a weighted sum of four metabolites from the TMAO pathway were risk markers for deterioration in renal function during long-term follow-up. Metabolites from the TMAO pathway were not independently related to risk of all-cause mortality or CVD.

Current and future therapies for type 1 diabetes.

In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.

Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial.

OBJECTIVE: A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS: LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5-5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (n = 2,928), 30-0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [<30 mg/g, 30-300 mg/g, or ≥300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes. RESULTS: For MACE, hazard ratios (HRs) for those with >30% and 30-0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS: A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.

Insulin at 100: still central in protein-based therapy for chronic disease.

The discovery of insulin has inspired several pivotal medical and scientific developments during the past 100 years. Here, we describe how insulin as a model protein will drive future advances in peptide- and protein-based therapies for chronic diseases.