Effect of semaglutide on kidney function across different levels of baseline HbA1c, blood pressure, body weight and albuminuria in SUSTAIN 6 and PIONEER 6.

BACKGROUND AND HYPOTHESIS: This post-hoc analysis explored the semaglutide effects on eGFR slope by baseline glycemic control, blood pressure (BP), body mass index (BMI), and albuminuria status in people with type 2 diabetes and high cardiovascular risk. METHODS: Pooled SUSTAIN 6 and PIONEER 6 data were analyzed for change in estimated glomerular filtration (eGFR) slope by baseline HbA1c (<8%/≥8%; <64 mmol/mol/≥64 mmol/mol), systolic BP (<140/90 mmHg/≥140/90 mmHg), and BMI (<30 kg/m2/≥30 kg/m2). SUSTAIN 6 data were analyzed by baseline urinary albumin: creatinine ratio (UACR; <30/30 - 300/>300 mg/g). RESULTS: The estimated absolute treatment differences (ETD) overall in eGFR slope [95% confidence intervals] favored semaglutide versus placebo in the pooled analysis (0.59 [0.29;0.89] mL/min/1.73m2/year) and in SUSTAIN 6 (0.60 [0.24;0.96] mL/min/1.73m2/year); the absolute benefit was consistent across all HbA1c, BP, BMI, and UACR subgroups (all p-interaction > 0.5). CONCLUSION: A clinically meaningful reduction in risk of chronic kidney disease progression was observed with semaglutide versus placebo regardless of HbA1c, BP, BMI, and UACR levels.

Cardiovascular and non-renal complications of chronic kidney disease: Managing risk.

Chronic kidney disease (CKD) currently affects approximately 850 million people globally and is continuing to increase in prevalence as well as in importance as a cause of death. The excess mortality related to CKD is mostly caused by an increase in cardiovascular disease. This includes atherosclerotic cardiovascular disease as many promoters of atherosclerosis, such as blood pressure, lipid levels and hypercoagulation, are increased in people with CKD. Diabetes is a leading cause of CKD contributing to the risk of CVD, and obesity is also increasingly prevalent. Management of these risk factors is therefore very important in CKD, and to reduce risk of CKD progression. Heart failure is also more prevalent in CKD and, again, many risk factors are shared. The concept of foundational pillars in the management of heart failure has been adapted to the treatment of CKD, with many organ-protective interventions, such renin-angiotensin system blockade, sodium-glucose cotransporter-2 inhibition and mineralocorticoid receptor antagonism, reducing the risk for mortality in heart failure with reduced ejection fraction, but also for progression of CKD. Atrial fibrillation is also more common with CKD and affects the management of the former. In this review these non-renal complications of CKD are discussed, along with how the risk of these complications should be managed. Many new opportunities have demonstrated heart and kidney organ protection, but implementation is a challenge.

The fibroblast hormone endotrophin is a biomarker of mortality in chronic diseases.

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PRO-C6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PRO-C6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N=15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95% CI 1.75-2.52) for a 2-fold increase in PRO-C6, with some heterogeneity observed between the studies (I2=70%). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.

Prevalence of Chronic Kidney Disease in Type 1 Diabetes Among Adults in the U.S.

OBJECTIVE: The prevalence of CKD in adults ≥18 years of age with type 1 diabetes in the U.S. was determined using National Health and Nutrition Examination Survey (NHANES) data. RESEARCH DESIGN AND METHODS: A modified treatment-based algorithm applying a subset of NHANES diabetes questionnaires was used. The number of respondents with CKD and type 1 diabetes was weighted (extrapolated) to the U.S. population. RESULTS: Based on data between 2015 and 2018, type 1 diabetes was identified in 47 out of 19,225 adults with evaluable kidney function data. CKD was present in 20 out of 47 people identified with type 1 diabetes. The weighted estimate of CKD in type 1 diabetes was 21.5%, corresponding to 258,196 (95% CI 71,189-445,203) people in the U.S. CONCLUSIONS: Applying a conservative approach in our study indicates that CKD is common in adults with type 1 diabetes in the U.S.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

New Diabetic Treatment by Alleviation of Autonomic Nervous System Dysfunction Measured as Periosteal Pressure Sensitivity at Sternum Improves Empowerment, Treatment Satisfaction, and Self-Reported Health of People with Type 2 Diabetes: A Randomized Trial.

Purpose: Autonomic nervous system dysfunction (ANSD), for which presently no treatment exists, has a negative impact on prognosis in people with type 2 diabetes (T2D). Periosteal pressure sensitivity (PPS) on sternum may be a measure of autonomic nervous system dysfunction (ANSD). We tested if a non-pharmacological PPS-feedback-guided treatment program based on non-noxious sensory nerve stimulation, known to reduce PPS, changed empowerment, treatment satisfaction, and quality of life in people with T2D, compared to usual treatment. Patients and Methods: Analysis of secondary endpoints in a single center, two-armed, parallel-group, observer-blinded, randomized controlled trial of individuals with T2D. Participants were randomized to non-pharmacological intervention as an add-on to treatment as usual. Endpoints were evaluated by five validated questionnaires: Diabetes specific Empowerment (DES-SF), Diabetes Treatment Satisfaction (DTSQ), quality of life (QOL) (WHO-5), clinical stress signs (CSS), and self-reported health (SF-36). Sample size calculation was based on the primary endpoint HbA1c. Results: We included 144 participants, 71 allocated to active intervention and 73 to the control group. Active intervention compared to control revealed improved diabetes-specific empowerment (p = 0.004), DTSQ (p = 0.001), and SF-36 self-reported health (p=0.003) and tended to improve quality of life (WHO-5) (p = 0.056). The findings were clinically relevant with a Cohen's effect size of 0.5 to 0.7. Conclusion: This non-pharmacological intervention, aiming to reduce PPS, and thus ANSD, improved diabetes-specific empowerment, treatment satisfaction, and self-reported health when compared to usual treatment. The proposed intervention may be a supplement to conventional treatment for T2D.

Association of multiple sclerosis with incident diabetes: A nationwide cohort study.

AIM: Diabetes mellitus (DM) and multiple sclerosis (MS) are two common diseases known to worsen the trajectory of each other, yet it is unknown whether MS is associated with incident DM. METHODS: Using Danish nationwide registries, we identified all patients aged 18-99 with a first-time primary or secondary discharge diagnosis with MS between 2000 and 2018, with no known DM. These patients were matched with control subjects from the background population in a 1:5 ratio based on age and sex, to assess their risk of DM. RESULTS: A total of 13,376 patients with MS and 66,880 matched control subjects were included (33 % men; median age, 42 years [25th-75th percentile, 33-51]). During a median follow-up of 8.3 years (25th-75th percentile, 4.0-13.3), 467 (3.5 %) patients with MS and 2397 (3.6 %) control subjects were diagnosed with DM. The cumulative incidence of DM was similar among patients with MS and control subjects (95 % confidence interval [CI] 6.5 % [5.7-7.2 %] vs. 7.3 % [95 % CI 6.9-7.9 %], respectively), and adjusted analysis yielded a hazard ratio (HR) of 0.98 [95 % CI 0.89-1.09]). The overall risk of incident type 1 diabetes was low and yielded a HR of 1.60 [95 % CI 0.98-1.40] in patients with MS compared with control subject (P = 0.07). CONCLUSION: This study demonstrated that patients with MS had a similar risk of incident DM as compared to age- and sex matched controls from the background population.

Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial.

People with type-2-diabetes (T2D) and chronic kidney disease (CKD), have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) independently reduce cardiovascular and kidney events. The effect of combining both is unclear. FLOW trial participants with T2D and CKD were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% eGFR reduction, kidney or cardiovascular death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide vs placebo (95% confidence interval [CI] 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (HR 1.07; 95% CI 0.69, 1.67; P=0.755), and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (HR 0.73; 0.63, 0.85; P<0.001; P-interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total eGFR slope (ml/min/1.73m2/year) were 0.75 (-0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in non-SGLT2i-subgroup, P-interaction 0.237. Semaglutide benefits on major cardiovascular events and all-cause death were similar regardless of SGLT2i use (P-interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 .

The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. METHODS: Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. RESULTS: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). CONCLUSION: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Multiple urinary peptides are associated with hypertension: a link to molecular pathophysiology.

OBJECTIVES: Hypertension is a common condition worldwide; however, its underlying mechanisms remain largely unknown. This study aimed to identify urinary peptides associated with hypertension to further explore the relevant molecular pathophysiology. METHODS: Peptidome data from 2876 individuals without end-organ damage were retrieved from the Human Urinary Proteome Database, belonging to general population (discovery) or type 2 diabetic (validation) cohorts. Participants were divided based on systolic blood pressure (SBP) and diastolic BP (DBP) into hypertensive (SBP ≥140 mmHg and/or DBP ≥90 mmHg) and normotensive (SBP <120 mmHg and DBP <80 mmHg, without antihypertensive treatment) groups. Differences in peptide abundance between the two groups were confirmed using an external cohort ( n  = 420) of participants without end-organ damage, matched for age, BMI, eGFR, sex, and the presence of diabetes. Furthermore, the association of the peptides with BP as a continuous variable was investigated. The findings were compared with peptide biomarkers of chronic diseases and bioinformatic analyses were conducted to highlight the underlying molecular mechanisms. RESULTS: Between hypertensive and normotensive individuals, 96 (mostly COL1A1 and COL3A1) peptides were found to be significantly different in both the discovery (adjusted) and validation (nominal significance) cohorts, with consistent regulation. Of these, 83 were consistently regulated in the matched cohort. A weak, yet significant, association between their abundance and standardized BP was also observed. CONCLUSION: Hypertension is associated with an altered urinary peptide profile with evident differential regulation of collagen-derived peptides. Peptides related to vascular calcification and sodium regulation were also affected. Whether these modifications reflect the pathophysiology of hypertension and/or early subclinical organ damage requires further investigation.

Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.

BACKGROUND: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. METHODS: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. RESULTS: Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). CONCLUSIONS: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.).

Contemporary prevalence of diabetic neuropathies in individuals with type 1 and type 2 diabetes in a Danish tertiary outpatient clinic.

BACKGROUND: Population-based prevalence estimates of distal symmetric polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN) are scares. Here we present neuropathy estimates and describe their overlap in a large cohort of people with type 1 and type 2 diabetes. METHODS: In a large population of outpatient participants, DPN was assessed using vibration perception threshold, sural nerve function, touch, pain and thermal sensation. Definite DPN was defined by the Toronto Consensus Criteria. Painful DPN was defined by Douleur Neuropathique 4 Questions. DAN measures were: cardiovascular reflex tests, electrochemical skin conductance, and gastroparesis cardinal symptom index. RESULTS: We included 822 individuals with type 1 (mean age (±SD) 54 ± 16 years, median [IQR] diabetes duration 26 [15-40] years) and 899 with type 2 diabetes (mean age 67 ± 11 years, median diabetes duration 16 [11-22] years). Definite DPN was prevalent in 54 % and 68 %, and painful DPN was in 5 % and 15 % of type 1 and type 2 participants, respectively. The prevalence of DAN varied between 6 and 39 % for type 1 and 9-49 % for type 2 diabetes. DPN without other neuropathy was present in 45 % with T1D and 50 % with T2D. CONCLUSION: The prevalence of DPN and DAN was high. DPN and DAN co-existed in only 50 % of cases.

Extracellular matrix turnover proteins as risk markers in people with type 2 diabetes and microalbuminuria.

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.

Circulating metabolomic markers in association with overall burden of microvascular complications in type 1 diabetes.

INTRODUCTION: Diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN) share common pathophysiology and pose an additive risk of early mortality. RESEARCH DESIGN AND METHODS: In adults with type 1 diabetes, 49 metabolites previously associated with either DR or DKD were assessed in relation to presence of DSPN. Metabolites overlapping in significance with presence of all three complications were assessed in relation to microvascular burden severity (additive number of complications-ie, presence of DKD±DR±DSPN) using linear regression models. Subsequently, the same metabolites were assessed with progression to endpoints: soft microvascular events (progression in albuminuria grade, ≥30% estimated glomerular filtration rate (eGFR) decline, or any progression in DR grade), hard microvascular events (progression to proliferative DR, chronic kidney failure, or ≥40% eGFR decline), and hard microvascular or macrovascular events (hard microvascular events, cardiovascular events (myocardial infarction, stroke, or arterial interventions), or cardiovascular mortality), using Cox models. All models were adjusted for sex, baseline age, diabetes duration, systolic blood pressure, HbA1c, body mass index, total cholesterol, smoking, and statin treatment. RESULTS: The full cohort investigated consisted of 487 participants. Mean (SD) follow-up was 4.8 (2.9, 5.7) years. Baseline biothesiometry was available in 202 participants, comprising the cross-sectional cohort. Eight metabolites were significantly associated with presence of DR, DKD, and DSPN, and six with additive microvascular burden severity. In the full cohort longitudinal analysis, higher levels of 3,4-dihydroxybutanoic acid (DHBA), 2,4-DHBA, ribonic acid, glycine, and ribitol were associated with development of events in both crude and adjusted models. Adding 3,4-DHBA, ribonic acid, and glycine to a traditional risk factor model improved the discrimination of hard microvascular events. CONCLUSIONS: While prospective studies directly assessing the predictive ability of these markers are needed, our results strengthen the role of clinical metabolomics in relation to risk assessment of diabetic complications in chronic type 1 diabetes.

Validation of the Klinrisk chronic kidney disease progression model in the FIDELITY population.

Background: Chronic kidney disease (CKD) affects >800 million individuals worldwide and is often underrecognized. Early detection, identification and treatment can delay disease progression. Klinrisk is a proprietary CKD progression risk prediction model based on common laboratory data to predict CKD progression. We aimed to externally validate the Klinrisk model for prediction of CKD progression in FIDELITY (a prespecified pooled analysis of two finerenone phase III trials in patients with CKD and type 2 diabetes). In addition, we sought to identify evidence of an interaction between treatment and risk. Methods: The validation cohort included all participants in FIDELITY up to 4 years. The primary and secondary composite outcomes included a ≥40% decrease in estimated glomerular filtration rate (eGFR) or kidney failure, and a ≥57% decrease in eGFR or kidney failure. Prediction discrimination was calculated using area under the receiver operating characteristic curve (AUC). Calibration plots were calculated by decile comparing observed with predicted risk. Results: At time horizons of 2 and 4 years, 993 and 1795 patients experienced a primary outcome event, respectively. The model predicted the primary outcome accurately with an AUC of 0.81 for 2 years and 0.86 for 4 years. Calibration was appropriate at both 2 and 4 years, with Brier scores of 0.067 and 0.115, respectively. No evidence of interaction between treatment and risk was identified for the primary composite outcome (P = .31). Conclusions: Our findings demonstrate the accuracy and utility of a laboratory-based prediction model for early identification of patients at the highest risk of CKD progression.

Ambient heat exposure and kidney function in patients with chronic kidney disease: a post-hoc analysis of the DAPA-CKD trial.

BACKGROUND: Higher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis. METHODS: DAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73 m2. In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS: Climate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m2; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days' heat index of more than 30°C was associated with a -0·6% (95% CI -0·9% to -0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m2 located in a very hot versus a temperate environment. INTERPRETATION: Higher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression. FUNDING: None.

Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Combination therapy for kidney disease in people with diabetes mellitus.

Diabetic kidney disease (DKD), defined as co-existing diabetes and chronic kidney disease in the absence of other clear causes of kidney injury, occurs in approximately 20-40% of patients with diabetes mellitus. As the global prevalence of diabetes has increased, DKD has become highly prevalent and a leading cause of kidney failure, accelerated cardiovascular disease, premature mortality and global health care expenditure. Multiple pathophysiological mechanisms contribute to DKD, and single lifestyle or pharmacological interventions have shown limited efficacy at preserving kidney function. For nearly two decades, renin-angiotensin system inhibitors were the only available kidney-protective drugs. However, several new drug classes, including sodium glucose cotransporter-2 inhibitors, a non-steroidal mineralocorticoid antagonist and a selective endothelin receptor antagonist, have now been demonstrated to improve kidney outcomes in people with type 2 diabetes mellitus. In addition, emerging preclinical and clinical evidence of the kidney-protective effects of glucagon-like-peptide-1 receptor agonists has led to the prospective testing of these agents for DKD. Research and clinical efforts are geared towards using therapies with potentially complementary efficacy in combination to safely halt kidney disease progression. As more kidney-protective drugs become available, the outlook for people living with DKD should improve in the next few decades.

Aldosterone synthase inhibitor (BI 690517) therapy for people with diabetes and albuminuric chronic kidney disease: A multicentre, randomized, double-blind, placebo-controlled, Phase I trial.

AIM: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. METHODS: Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. RESULTS: Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. CONCLUSIONS: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).