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Background A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. Methods Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes. Results Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211–0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33–0.76], 0.62 [0.45–0.85], and 0.64 [0.49–-0.83], respectively; p -interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p -interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p -interaction = 0.63), and all-cause mortality (p -interaction p  = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively). Conclusions The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety. [ABSTRACT FROM AUTHOR]

Following propensity-score matching, there were 6477 patients in each arm; 5431 patients (41.9%) were women and the mean (SD) patient age was 59.8 (10.9) years (Table 1). Patients with T2D, who initiated an SGLT2 inhibitor (empagliflozin or dapagliflozin) in an outpatient setting between August 2015 and December 2020 were propensity-scored matched with patients starting a DPP-4 inhibitor (sitagliptin, linagliptin, vildagliptin or saxagliptin). Risk of hospitalization with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes lacking evidence of chronic kidney disease: Real-world data Patients with type 2 diabetes (T2D) have a high incidence of hospitalizations that reduce patients' quality of life and are translated into a significant burden on healthcare systems, accompanied by increased costs.[[1]] Randomized controlled trials (RCTs) showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular events, heart failure (HF) hospitalizations, and kidney outcomes in patients with T2D, HF, or chronic kidney disease (CKD).[3] In some of these RCTs, SGLT2 inhibitors also modestly reduced the risk for any hospitalization.[[4], [6], [8], [10]] However, these studies included patients with T2D and high cardiovascular risk,[[4], [6], [11]] or patients with CKD with and without T2D.[[8]] Whether SGLT2 inhibitor use is associated with a lower risk for any hospitalization in a general population of patients with T2D, especially patients without CKD, is unknown. [Extracted from the article]

Background: Acute hospitalizations are common in patients with chronic kidney disease (CKD) and often lead to decreases in health-related quality of life and increased care costs.Objective: To determine the effects of dapagliflozin on first hospitalizations and all (first and subsequent) hospitalizations and to explore effects on cause-specific hospitalizations.Design: Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT03036150).Setting: 386 ambulatory practice sites in 21 countries from 2 February 2017 through 12 June 2020.Participants: Adults with an estimated glomerular filtration rate of 25 to 75 mL/min/1.73 m2 and a urinary albumin-creatinine ratio of 200 to 5000 mg/g, with and without type 2 diabetes.Intervention: Dapagliflozin, 10 mg once daily, or matching placebo (1:1 ratio).Measurements: The effects of dapagliflozin on first hospitalizations for any cause, all hospitalizations, and cause-specific (first and recurrent) hospitalizations were determined. The reported system organ class was used to evaluate reasons for admission. Hospitalizations were analyzed using Cox proportional hazards regression models (first hospitalization), the Lin-Wei-Yang-Ying method (all hospitalizations or death), and negative binomial models (cause-specific hospitalizations).Results: The study included 4304 patients (mean age, 61.8 years; 33.1% women). During a median follow-up of 2.4 years, 2072 hospitalizations were reported among 1224 (28.4%) participants. Compared with placebo, dapagliflozin reduced risk for a first hospitalization (hazard ratio, 0.84 [95% CI, 0.75 to 0.94]) and all hospitalizations or death (rate ratio, 0.79 [CI, 0.70 to 0.89]). There was no evidence that the effects of dapagliflozin on first and all hospitalizations varied by baseline presence of type 2 diabetes (P for interaction = 0.60 for each). Compared with placebo, dapagliflozin reduced the rate of admissions due to cardiac disorders, renal and urinary disorders, metabolism and nutrition disorders, and neoplasms.Limitations: This was a post hoc analysis and should be viewed as hypothesis-generating. Hospitalizations and causes were reported by site investigators and were not centrally adjudicated.Conclusion: Dapagliflozin reduced the risk for hospitalization for any cause in patients with CKD with and without type 2 diabetes.Primary Funding Source: AstraZeneca. [ABSTRACT FROM AUTHOR]

Objective: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6.Research Design and Methods: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model.Results: The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively.Conclusions: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6-lowering therapy on CV, kidney, and safety outcomes remains to be tested. [ABSTRACT FROM AUTHOR]

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex. Methods: This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR < 60 mL/min/1.73 m2 were defined as within the diabetes-cardio-renal (DCR) spectrum. Results: Overall, 1,389,604 subjects (52.2% females) were included; 445,477 (32.1%) were 25– < 40 years, 468,273 (33.7%) were 40– < 55 years, and 475,854 (34.2%) were ≥ 55 years old. eGFR measurements were available in 74.7% of the participants and in over 97% of those with T2D or HF. eGFR availability increased in older age groups. There were 140,636 (10.1%) patients with T2D, 54,187 (3.9%) with eGFR < 60 mL/min/1.73m2, and 11,605 (0.84%) with HF. Overall, 12.6% had at least one condition within the DCR spectrum, 2.0% had at least two, and 0.23% had all three. Cardiorenal syndrome (both HF and eGFR < 60 mL/min/1.73m2) was prevalent in 0.40% of the entire population and in 2.3% of those with T2D. In patients with both HF and T2D, 55.2% had eGFR < 60 mL/min/1.73m2 and 15.8% had eGFR < 30 mL/min/1.73m2. Amongst those within the DCR spectrum, T2D was prominent in younger participants, but was gradually replaced by HF and eGFR < 60 mL/min/1.73m2 with increasing age. The congruence between all three conditions increased with age. Conclusions: This large, broad-based study provides a contemporary, high-resolution prevalence of the DCR spectrum and its components. The results highlight differences in dominance and degree of congruence between T2D, HF, and kidney dysfunction across ages. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) are at increased risk for hospital admissions, and acute hospitalizations are associated with a worse prognosis. However, outcomes related to all‐cause hospital admissions (ACHAs) were often overlooked in trials that demonstrated the cardiovascular and kidney benefits of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs). This review includes a contemporary literature summary of emerging data regarding the effects of SGLT2 inhibitors and GLP‐1RAs on ACHAs. The role of SGLT2 inhibitors in preventing ACHAs was shown in exploratory investigations of several randomized controlled trials (RCTs) and was further supported by real‐world evidence (RWE). However, the association between GLP‐1RA use and lower ACHA risk was mainly shown through RWE, with minimal available RCT data. We also discuss the advantages and challenges of studying ACHAs. Finally, we propose an easily memorized ("ABCDE" acronym) clinical approach to evaluating T2D status and treatment in admitted patients, as they transition from hospital to community care. This systematic approach may assist clinicians in recognizing possible pitfalls in T2D management, thereby preventing subsequent hospitalizations and improving patient prognoses. While acute admission can sometimes be perceived as a management failure, it should also be viewed as an opportunity to take action to prevent the next hospitalization. [ABSTRACT FROM AUTHOR]

Context: Thyroid hormones play a key role in systemic metabolism, yet the relationship between thyroid dysfunction and risk for type 2 diabetes is unclear.Objective: To assess type 2 diabetes risk in adulthood among adolescents with thyroid disorders.Design and Setting: A nationwide, population-based study of Israeli adolescents who were examined before military recruitment during 1988 to 2007 and were followed until December 31, 2016.Participants: 1 382 560 adolescents (mean age 17.3 years).Interventions: The diagnosis of thyroid disorders was based on recent thyroid function tests. Data were linked to the Israeli National Diabetes Registry. Cox proportional hazard models were applied.Main Outcome Measures: Type 2 diabetes incidence.Results: During a mean follow-up of 18.5 years, 1.12% (69 of 6,152) of adolescents with thyroid disorders were diagnosed with type 2 diabetes vs 0.77% of adolescents without thyroid disorders. The hazard ratio (HR) for type 2 diabetes was 2.3 (95% CI, 1.8-2.9) among those with thyroid disorders, after adjustment for sex, birth-year, body mass index, and sociodemographic confounders. The increased diabetes risk was observed in both men and women, with the presence or absence of obesity, and in the absence of other health conditions and was associated with different types of thyroid disorders. It was also similar when the outcome was defined as type 2 diabetes diagnosed at or before the age of 30 years (HR 2.3, 95% CI, 1.5-3.5).Conclusions: Thyroid disorders diagnosed in adolescence are a risk factor for early-onset type 2 diabetes in both men and women. [ABSTRACT FROM AUTHOR]

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.Research Design and Methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480).Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]