Empagliflozin and Risk of Incident Gout: Analysis from the EMPagliflozin Comparative Effectiveness and SafEty (EMPRISE) Cohort Study.

BACKGROUND: Hyperuricemia is frequently observed in patients with type 2 diabetes (T2D) and is associated with increased risk of gout and cardiovascular disease (CVD). Empagliflozin lowers serum urate levels by enhancing its urinary excretion. OBJECTIVE: To compare initiators of empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP4i) and initiators of empagliflozin vs glucagon-like peptide-1 receptor agonist (GLP-1RA) with respect to the risk of incident gout events. DESIGN AND PARTICIPANTS: Using three claims-based datasets from 08/2014 to 09/2019, we generated two cohorts (cohort 1: empagliflozin vs DPP4i; cohort 2: empagliflozin vs GLP-1RA) of adult patients with T2D and without prior history of gout or gout-specific medication dispensing separately in each dataset. To assess the risk of incident gout, we estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years (PY) with their 95% confidence intervals (CI) before and after 1:1 propensity score (PS) matching adjusting for 141 baseline covariates. KEY RESULTS: We identified 102,262 pairs of 1:1 propensity score-matched adults in cohort 1 and 131,216 pairs in cohort 2. Over a mean follow-up period of 8 months on treatment, the risk of gout was lower in patients initiating empagliflozin compared to DPP4i (HR = 0.69: 95% CI (0.60-0.79); RD = - 2.27: 95% CI (- 3.08, 1.46)) or GLP-1RA (HR = 0.83: 95% CI (0.73-0.94); RD = - 0.99: 95% CI (- 1.66, - 0.32)). Results were consistent across subgroups (sex, age, body mass index, chronic kidney disease, heart failure, cardiovascular disease, and concurrent diuretic use) and sensitivity analyses. CONCLUSIONS: Among adults with T2D, the initiation of empagliflozin vs a DPP4i or GLP-1RA was associated with lower risk of incident gout, complementing results from a post hoc analysis of the EMPA-REG OUTCOME trial and previously published observational research focusing on the sodium-glucose co-transporter-2 inhibitor class in more narrowly defined study populations.

Effectiveness and safety of empagliflozin: final results from the EMPRISE study.

AIMS/HYPOTHESIS: Limited evidence exists on the comparative safety and effectiveness of empagliflozin against alternative glucose-lowering medications in individuals with type 2 diabetes with the broad spectrum of cardiovascular risk. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) cohort study was designed to monitor the safety and effectiveness of empagliflozin periodically for a period of 5 years with data collection from electronic healthcare databases. METHODS: We identified individuals ≥18 years old with type 2 diabetes who initiated empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP-4i) from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we identified four a priori-defined effectiveness outcomes: (1) myocardial infarction (MI) or stroke; (2) hospitalisation for heart failure (HHF); (3) major adverse cardiovascular events (MACE); and (4) cardiovascular mortality or HHF. Safety outcomes included lower-limb amputations, non-vertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), severe hypoglycaemia, retinopathy progression, and short-term kidney and bladder cancers. We estimated HRs and rate differences (RDs) per 1000 person-years, overall and stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD) and heart failure. RESULTS: We identified 115,116 matched pairs. Compared with DPP-4i, empagliflozin was associated with lower risks of MI/stroke (HR 0.88 [95% CI 0.81, 0.96]; RD -2.08 [95% CI (-3.26, -0.90]), HHF (HR 0.50 [0.44, 0.56]; RD -5.35 [-6.22, -4.49]), MACE (HR 0.73 [0.62, 0.86]; RD -6.37 [-8.98, -3.77]) and cardiovascular mortality/HHF (HR 0.57 [0.47, 0.69]; RD -10.36 [-12.63, -8.12]). Absolute benefits were larger in older individuals and in those with ASCVD/heart failure. Empagliflozin was associated with an increased risk of DKA (HR 1.78 [1.44, 2.19]; RD 1.59 [1.08, 2.09]); decreased risks of AKI (HR 0.62 [0.54, 0.72]; RD -2.39 [-3.08, -1.71]), hypoglycaemia (HR 0.75 [0.67, 0.84]; RD -2.46 [-3.32, -1.60]) and retinopathy progression (HR 0.78 [0.63, 0.96)]; RD -9.49 [-16.97, -2.10]); and similar risks of other safety events. CONCLUSIONS/INTERPRETATION: Empagliflozin relative to DPP-4i was associated with risk reductions of MI or stroke, HHF, MACE and the composite of cardiovascular mortality or HHF. Absolute risk reductions were larger in older individuals and in those who had history of ASCVD or heart failure. Regarding the safety outcomes, empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy, with no difference in the short-term risks of lower-extremity amputation, non-vertebral fractures, kidney and renal pelvis cancer, and bladder cancer.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study.

BACKGROUND: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups. METHODS: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). RESULTS: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex. CONCLUSIONS: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes.

Importance: Type 2 diabetes (T2D) is associated with an increased risk of kidney stones. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) might lower the risk of nephrolithiasis by altering urine composition. However, no studies have investigated the association between SGLT2i use and nephrolithiasis risk in patients receiving routine care in the US. Objective: To investigate the association between SGLT2i use and nephrolithiasis risk in clinical practice. Design, Setting, and Participants: This new-user, active comparator cohort study used data from commercially insured adults (aged ≥18 years) with T2D who initiated treatment with SGLT2is, glucagon-like peptide 1 receptor agonists (GLP-1RAs), or dipeptidyl peptidase 4 inhibitors (DPP4is) between April 1, 2013, and December 31, 2020. The data were analyzed from July 2021 through June 2023. Exposure: New initiation of an SGLT2i, GLP-1RA, or DPP4i. Main Outcomes and Measures: The primary outcome was nephrolithiasis diagnosed by International Classification of Diseases codes in the inpatient or outpatient setting. New SGLT2i users were 1:1 propensity score matched to new users of a GLP-1RA or DPP4i in pairwise comparisons. Incidence rates, rate differences (RDs), and estimated hazard ratios (HRs) with 95% CIs were calculated. Results: After 1:1 propensity score matching, a total of 716 406 adults with T2D (358 203 pairs) initiating an SGLT2i or a GLP-1RA (mean [SD] age, 61.4 [9.7] years for both groups; 51.4% vs 51.2% female; 48.6% vs 48.5% male) and 662 056 adults (331 028 pairs) initiating an SGLT2i or a DPP4i (mean [SD] age, 61.8 [9.3] vs 61.7 [10.1] years; 47.4% vs 47.3% female; 52.6% vs 52.7% male) were included. Over a median follow-up of 192 (IQR, 88-409) days, the risk of nephrolithiasis was lower in patients initiating an SGLT2i than among those initiating a GLP-1RA (14.9 vs 21.3 events per 1000 person-years; HR, 0.69 [95% CI, 0.67-0.72]; RD, -6.4 [95% CI, -7.1 to -5.7]) or a DPP4i (14.6 vs 19.9 events per 1000 person-years; HR, 0.74 [95% CI, 0.71-0.77]; RD, -5.3 [95% CI, -6.0 to -4.6]). The association between SGLT2i use and nephrolithiasis risk was similar by sex, race and ethnicity, history of chronic kidney disease, and obesity. The magnitude of the risk reduction with SGLT2i use was larger among adults aged younger than 70 years vs aged 70 years or older (HR, 0.85 [95% CI, 0.79-0.91]; RD, -3.46 [95% CI, -4.87 to -2.05] per 1000 person-years; P for interaction <.001). Conclusions and Relevance: These findings suggest that in adults with T2D, SGLT2i use may lower the risk of nephrolithiasis compared with GLP-1RAs or DPP4is and could help to inform decision-making when prescribing glucose-lowering agents for patients who may be at risk for developing nephrolithiasis.

Comparative Safety and Effectiveness of Warfarin or Rivaroxaban Versus Apixaban in Patients With Advanced CKD and Atrial Fibrillation: Nationwide US Cohort Study.

RATIONALE & OBJECTIVE: Head-to-head data comparing the effectiveness and safety of oral anticoagulants in patients with atrial fibrillation (AF) and advanced chronic kidney disease (CKD) are lacking. We compared the safety and effectiveness of warfarin or rivaroxaban versus apixaban in patients with AF and non-dialysis-dependent CKD stage 4/5. STUDY DESIGN: Propensity score-matched cohort study. SETTING & PARTICIPANTS: 2 nationwide US claims databases, Medicare and Optum's deidentified Clinformatics Data Mart Database, were searched for the interval from January 1, 2013, through March 31, 2022, for patients with nonvalvular AF and CKD stage 4/5 who initiated warfarin versus apixaban (matched cohort, n=12,488) and rivaroxaban versus apixaban (matched cohort, n = 5,720). EXPOSURES: Warfarin, rivaroxaban, or apixaban. OUTCOMES: Primary outcomes included major bleeding and ischemic stroke. Secondary outcomes included all-cause mortality, major gastrointestinal bleeding, and intracranial bleeding. ANALYTICAL APPROACH: Cox regression was used to estimate HRs, and 1:1 propensity-score matching was used to adjust for 80 potential confounders. RESULTS: Compared with apixaban, warfarin initiation was associated with a higher rate of major bleeding (HR, 1.85; 95% CI, 1.59-2.15), including major gastrointestinal bleeding (1.86; 1.53-2.25) and intracranial bleeding (2.15; 1.42-3.25). Compared with apixaban, rivaroxaban was also associated with a higher rate of major bleeding (1.69; 1.33-2.15). All-cause mortality was similar for warfarin (1.08; 0.98-1.18) and rivaroxaban (0.94; 0.81-1.10) versus apixaban. Furthermore, no statistically significant differences for ischemic stroke were observed for warfarin (1.14; 0.83-1.57) or rivaroxaban (0.71; 0.40-1.24) versus apixaban, but the CIs were wide. Similar results were observed for warfarin versus apixaban in the positive control cohort of patients with CKD stage 3, consistent with randomized trial findings. LIMITATIONS: Few ischemic stroke events, potential residual confounding. CONCLUSIONS: In patients with AF and advanced CKD, rivaroxaban and warfarin were associated with higher rates of major bleeding compared with apixaban, suggesting a superior safety profile for apixaban in this high-risk population. PLAIN-LANGUAGE SUMMARY: Different anticoagulants have been shown to reduce the risk of stroke in patients with atrial fibrillation, such as warfarin and direct oral anticoagulants like apixaban and rivaroxaban. Unfortunately, the large-scale randomized trials that compared direct anticoagulants versus warfarin excluded patients with advanced chronic kidney disease. Therefore, the comparative safety and effectiveness of warfarin, apixaban, and rivaroxaban are uncertain in this population. In this study, we used administrative claims data from the United States to answer this question. We found that warfarin and rivaroxaban were associated with increased risks of major bleeding compared with apixaban. There were few stroke events, with no major differences among the 3 drugs in the risk of stroke. In conclusion, this study suggests that apixaban has a better safety profile than warfarin and rivaroxaban.

Stratified analysis in comparative effectiveness studies that emulate randomized trials.

PURPOSE: For observational cohort studies that employ matching by propensity scores (PS), preliminary stratification by consequential predictors of outcome better emulates stratified randomization and potentially reduces variance and bias through relaxed dependence on modeling assumptions. We assessed the impact of pre-stratification in two real-life examples. For both, prior evidence from placebo-controlled randomized clinical trials (RCTs) suggested small or no risk reduction, but observational analysis suggested protection, presumably the result of confounding bias. STUDY DESIGN AND SETTING: The study populations consisted of Medicare beneficiaries (2014-18) with type 2 diabetes initiating either (i) empagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or (ii) empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA). The outcome was myocardial infarction or stroke. We estimated hazard ratios (HR) and rate differences (RD) after controlling for 143 pre-exposure covariates via 1:1 PS matching after (1) PS estimation in the total cohort (total-cohort PS-matching) and (2) PS estimation separately by baseline cardiovascular disease (stratified PS matching). RESULTS: Stratified PS matching resulted in HRs that exceeded those from total-cohort PS-matching by 13% and 9%, respectively, for the comparisons of empagliflozin to DPP-4i and GLP-1RA. Against both comparators, HRs and RDs after stratified PS matching were closer to the null, with slightly higher variances (2%-3%) than those after total-cohort PS matching. CONCLUSION: Stratified PS matching produced effect estimates closer to the expected trial findings than total-cohort PS matching. The price paid in increased variance was minimal.

A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes.

Hyperkalemia is a common adverse event in patients with chronic kidney disease (CKD) and type 2 diabetes and limits the use of guideline-recommended therapies such as renin-angiotensin system inhibitors. Here, we evaluated the comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of hyperkalemia. We conducted a population-based active-comparator, new-user cohort study using claims data from Medicare and two large United States commercial insurance databases (April 2013-April 2022). People with CKD stages 3-4 and type 2 diabetes who newly initiated SGLT-2i vs. DPP-4i (141671 patients), GLP-1RA vs. DPP-4i (159545 patients) and SGLT-2i vs. GLP-1RA (93033 patients) were included. The primary outcome was hyperkalemia diagnosed in inpatient or outpatient settings. Secondary outcomes included hyperkalemia diagnosed in inpatient or emergency department setting, and serum potassium levels of 5.5 mmol/L or more. Pooled hazard ratios and rate differences were estimated after propensity score matching to adjust for over 140 potential confounders. Initiation of SGLT-2i was associated with a lower risk of hyperkalemia compared with DPP-4i (hazard ratio 0.74; 95% confidence interval 0.68-0.80) and contrasted to GLP-1RA (0.92; 0.86-0.99). Compared with DPP-4i, GLP-1RA were also associated with a lower risk of hyperkalemia (0.80; 0.75-0.86). Corresponding absolute rate differences/1000 person-years were -24.8 (95% confidence interval -31.8 to -17.7), -5.0 (-10.9 to 0.8), and -17.7 (-23.4 to -12.1), respectively. Similar findings were observed for the secondary outcomes, among subgroups, and across single agents within the SGLT-2i and GLP-1RA classes. Thus, SGLT-2i and GLP-1RA are associated with a lower risk of hyperkalemia than DPP-4i in patients with CKD and type 2 diabetes, further supporting the use of these drugs in this population.

Statins, Mortality, and Major Adverse Cardiovascular Events Among US Veterans With Chronic Kidney Disease.

Importance: There are limited data for the utility of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and death in adults with chronic kidney disease (CKD). Objective: To evaluate the association of statin use with all-cause mortality and major adverse cardiovascular events (MACE) among US veterans older than 65 years with CKD stages 3 to 4. Design, Setting, and Participants: This cohort study used a target trial emulation design for statin initiation among veterans with moderate CKD (stages 3 or 4) using nested trials with a propensity weighting approach. Linked Veterans Affairs (VA) Healthcare System, Medicare, and Medicaid data were used. This study considered veterans newly diagnosed with moderate CKD between 2005 and 2015 in the VA, with follow-up through December 31, 2017. Veterans were older than 65 years, within 5 years of CKD diagnosis, had no prior ASCVD or statin use, and had at least 1 clinical visit in the year prior to trial baseline. Eligibility criteria were assessed for each nested trial, and Cox proportional hazards models with bootstrapping were run. Analysis was conducted from July 2021 to October 2023. Exposure: Statin initiation vs none. Main Outcomes and Measures: Primary outcome was all-cause mortality; secondary outcome was time to first MACE (myocardial infarction, transient ischemic attack, stroke, revascularization, or mortality). Results: Included in the analysis were 14 828 veterans. Mean (SD) age at CKD diagnosis was 76.9 (8.2) years, 14 616 (99%) were men, 10 539 (72%) White, and 2568 (17%) Black. After expanding to person-trials and assessing eligibility at each baseline, there were 151 243 person-trials (14 685 individuals) of nonstatin initiators and 2924 person-trials (2924 individuals) of statin initiators included. Propensity score adjustment via overlap weighting with nonparametric bootstrapping resulted in covariate balance, with mean (SD) follow-up of 3.6 (2.7) years. The hazard ratio for all-cause mortality was 0.91 (95% CI, 0.85-0.97) comparing statin initiators to noninitiators. The hazard ratio for MACE was 0.96 (95% CI, 0.91-1.02). Results remained consistent in prespecified subgroup analyses. Conclusions and Relevance: In this target trial emulation of statin initiation in US veterans older than 65 years with CKD stages 3 to 4 and no prior ASCVD, statin initiation was significantly associated with a lower risk of all-cause mortality but not MACE. Results should be confirmed in a randomized clinical trial.

Types of dairy foods and risk of fragility fracture in the prospective Nurses' Health Study cohort.

BACKGROUND: Fragility fractures present enormous health challenges for women. Dairy products provide many bone-beneficial nutrients, such as calcium and vitamin D. Individual dairy foods may exert different effects on bone health. OBJECTIVES: The aim of this study was to investigate the associations between total dairy, yogurt, milk, and cheese and fragility fracture risk among females in the prospective Nurses' Health Study (NHS) conducted in the United States. METHODS: In the current analysis, 103,003 females with mean age of 48 y were followed from 1980-2004. Proportional hazards models were used to estimate risk of first fracture (of the wrist, hip, or vertebrae) by intakes of dairy foods (total dairy, milk, yogurt, or cheese) obtained from a food frequency questionnaire. Fractures that were caused by high-trauma events were not included. We relied on self-reported data for wrist and hip fractures whereas for vertebral fractures, medical records were used to confirm cases. RESULTS: A total of 5495 incident fracture cases were documented during follow-up. After controlling for relevant confounding variables, consumption of ≥2 servings/d of total dairy (compared with <1 serving/d) was associated with lower fracture risk (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.61, 0.89). More than 2 servings of milk per day (compared with <1 serving/d) were associated with a lower fracture risk (HR: 0.85; 95% CI: 0.77, 0.94). Intakes of calcium, vitamin D, and protein from nondairy sources did not modify the effects of total dairy or milk on fracture risk. There was no association between yogurt intake and fracture risk. Intake of cheese (≥1 servings/d compared with <1 serving/wk) was weakly associated with lower fracture risk (HR: 0.89; 95% CI: 0.79, 0.99). CONCLUSIONS: Higher total dairy, milk, and cheese intakes are associated with lower risks of fracture in females in the NHS.

What matters most to older adults: Racial and ethnic considerations in values for current healthcare planning.

BACKGROUND: Clarifying what matters most informs current care planning for adults with multiple comorbidities. We describe how adults aged 55+ rate what matters most and differences in Black and White participants. METHODS: Participants (N = 247, Age M = 63.61 ± 5.26) who self-identified as Black (n = 89), White (n = 96), or other racial and ethnic groups (n = 62) completed an online survey. Healthcare values in four domains, (1) important factors for managing health, (2) functioning, (3) enjoying life, and (4) connecting, were assessed with the What Matters Most-Structured Tool. Frailty was assessed with the FRAIL scale. RESULTS: Concerns about pain and finances were rated as the most influential when making healthcare decisions across groups. Black participants rated religious and racial, ethnic, and cultural considerations as more important in healthcare decision-making than did White participants (Black participant M = 1.93 ± 0.85 vs. White participant M = 1.26 ± 0.52), citing concerns about health equity, disparity, and representation. Across the sample, specific aspects of functioning (e.g., ability to think clearly, walk, and see) and connecting (e.g., with family and friends and with God) were highly valued. Black participants rated the ability to dress or bathe, exercise, and connect with God as more important than did White participants, and they were also more likely to rate length of life as more important relative to quality of life. Value ratings were not associated with other demographic or health factors. CONCLUSIONS: Adults aged 55+ from diverse groups highly value functioning and connections when making health decisions, with important contextual distinctions between Black participants and White participants. This study population was relatively young; future studies in older populations are needed.

Contemporary trends in the utilization of second-line pharmacological therapies for type 2 diabetes in the United States and the United Kingdom.

AIM: To examine trends of second-line glucose-lowering therapies among patients with type 2 diabetes (T2D) initiating first-line metformin in the United States and the United Kingdom, overall and by subgroups of cardiovascular disease (CVD) and calendar time. METHODS: Using the US Optum Clinformatics and the UK Clinical Practice Research Datalink, we identified adults with T2D who initiated first-line metformin or sulphonylurea monotherapy, separately, from 2013 to 2019. Within both cohorts, we identified patterns of second-line medications through June 2021. We stratified patterns by CVD and calendar time to investigate the impact of rapidly evolving treatment guidelines. RESULTS: We identified 148 511 and 169 316 patients initiating treatment with metformin monotherapy in the United States and the United Kingdom, respectively. Throughout the study period, sulphonylureas and dipeptidyl peptidase-4 inhibitors were the most frequently initiated second-line medications in the United States (43.4% and 18.2%, respectively) and the United Kingdom (42.5% and 35.8%, respectively). After 2018, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists were more commonly used as second-line agents in the United States and the United Kingdom, although these agents were not preferentially prescribed among patients with CVD. Initiation of first-line sulphonylureas was much less common, and most sulphonylurea initiators had metformin added as the second-line agent. CONCLUSIONS: This international cohort study shows that sulphonylureas remain the most common second-line medications prescribed following metformin in both the United States and the United Kingdom. Despite recommendations, the use of newer glucose-lowering therapies with cardiovascular benefits remains low.

Nurse-led supportive Coordinated Transitional Care (CTraC) program improves care for veterans with serious illness.

BACKGROUND: The Coordinated Transitional Care (CTraC) program is a telephone-based, nurse-driven program shown to decrease readmissions. The aim of this project was to implement and evaluate an adapted version of CTraC, Supportive CTraC, to improve the quality of transitional and end-of-life care for veterans with serious illness. METHODS: We used the Replicating Effective Programs framework to guide adaptation and implementation. An RN nurse case manager (NCM) with experience in geriatrics and palliative care worked closely with inpatient and outpatient care teams to coordinate care. Eligible patients had a life-limiting diagnosis with substantial functional impairment and were not enrolled in hospice. The NCM identified veterans at VA Boston Healthcare System during an acute admission and delivered a protocolized intervention to define care needs and preferences, align care with patient values, optimize discharge plans, and provide ongoing, intensive phone-based case management. To evaluate efficacy, we matched each Supportive CTraC enrollee 1:1 to a contemporary comparison subject by age, risk of death or hospitalization, and discharge diagnosis. We used Kaplan-Meier plots and Cox-Proportional Hazards models to evaluate outcomes. Outcomes included palliative and hospice care use, acute care use, Massachusetts Medical Orders for Life Sustaining Treatment documentation, and survival. RESULTS: The NCM enrolled 104 veterans with high protocol fidelity. Over 1.5 years of follow-up, Supportive CTraC enrollees were 61% more likely to enroll in hospice than the comparison group (n = 57 vs. 39; HR = 1.61; 95% CI = 1.07-2.43). While overall acute care use was similar between groups, Supportive CTraC patients had fewer ICU admissions (n = 36 vs. 53; p = 0.005), were more likely to die in hospice (53 vs. 34; p = 0.008), and twice as likely to die at home with hospice (32.0 vs. 15.5; p = 0.02). There was no difference in survival between groups. CONCLUSIONS: A nurse-driven transitional care program for veterans with serious illness is feasible and effective at improving end-of-life outcomes.

Safety of SGLT2i with regard to bone and mineral metabolism in patients with CKD.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a relatively new class of oral glucose-lowering agents that reduce adverse cardiovascular and kidney outcomes among individuals with chronic kidney disease (CKD). Emerging evidence suggests that SGLT2i may also affect bone and mineral metabolism. This review analyzes recent evidence on the safety of SGLT2i with respect to bone and mineral metabolism in people with CKD, and discusses potential underlying mechanisms and clinical implications. RECENT FINDINGS: Recent studies have documented the beneficial effects of SGLT2i on cardiovascular and renal outcomes among individuals with CKD. SGLT2i may alter renal tubular phosphate reabsorption and are associated with increased serum concentrations of phosphate, fibroblast growth factor-23 (FGF-23), parathyroid hormone (PTH), decreased 1,25-hydroxyvitamin D levels, as well as increased bone turnover. Clinical trials have not demonstrated an increased risk of bone fracture associated with SGLT2i use among patients with CKD with or without diabetes mellitus. SUMMARY: Although SGLT2i are associated with abnormalities of bone and mineral metabolism, they have not been linked to a higher risk of fracture among patients with CKD. More research is needed on the association between SGLT2i and fracture risk in this population.

Risk of Severe Hypoglycemia With Newer Second-line Glucose-lowering Medications in Older Adults With Type 2 Diabetes Stratified by Known Indicators of Hypoglycemia Risk.

BACKGROUND: Severe hypoglycemia is associated with adverse clinical outcomes. We evaluated the risk of severe hypoglycemia in older adults initiating newer glucose-lowering medications overall and across strata of known indicators of high hypoglycemia risk. METHODS: We conducted a comparative-effectiveness cohort study of older adults aged >65 years with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA) using Medicare claims (3/2013-12/2018) and Medicare-linked-electronic health records. We identified severe hypoglycemia requiring emergency or inpatient visits using validated algorithms. After 1:1 propensity score matching, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years. Analyses were stratified by baseline insulin, sulfonylurea, cardiovascular disease (CVD), chronic kidney disease (CKD), and frailty. RESULTS: Over a median follow-up of 7 (interquartile range: 4-16) months, SGLT2i was associated with a reduced risk of hypoglycemia versus DPP-4i (HR 0.75 [0.68, 0.83]; RD -3.21 [-4.29, -2.12]), and versus GLP-1RA (HR 0.90 [0.82, 0.98]; RD -1.33 [-2.44, -0.23]). RD for SGLT2i versus DPP-4i was larger in patients using baseline insulin than in those not, although HRs were similar. In patients using baseline sulfonylurea, the risk of hypoglycemia was lower in SGLT2i versus DPP-4i (HR 0.57 [0.49, 0.65], RD -6.80 [-8.43, -5.16]), while the association was near-null in those without baseline sulfonylurea. Results stratified by baseline CVD, CKD and frailty were similar to the overall cohort findings. Findings for the GLP-1RA comparison were similar. CONCLUSIONS: SGLT2i was associated with a lower hypoglycemia risk versus incretin-based medications, with larger associations in patients using baseline insulin or sulfonylurea.

Accuracy of GFR Estimating Equations in Patients with Discordances between Creatinine and Cystatin C-Based Estimations.

SIGNIFICANCE STATEMENT: Large discordances between eGFR on the basis of creatinine (eGFR cr ) or cystatin C (eGFR cys ) are common in clinical practice. However, which GFR estimating equation (eGFR cr , eGFR cys , or eGFR cr-cys ) is most accurate in these settings is not known. In this real-world study of 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance, all three equations performed similarly when eGFR cr and eGFR cys were similar (45% of cases). However, with large discordances (55% of cases), eGFR cr-cys was much more accurate than either alone. These findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer who have been underrepresented in research cohorts. Thus, when eGFR cr and eGFR cys are largely discordant in clinical practice, eGFR cr-cys is more accurate than eGFR cr or eGFR cys . BACKGROUND: Cystatin C is recommended as a confirmatory test to eGFR when more precise estimates are needed for clinical decision making. Although eGFR on the basis of both creatinine and cystatin (eGFR cr-cys ) is the most accurate estimate in research studies, it is uncertain whether this is true in real-world settings, particularly when there are large discordances between eGFR based on creatinine (eGFR cr ) and that based on cystatin C (eGFR cys ). METHODS: We included 6185 adults referred for measured GFR (mGFR) using plasma clearance of iohexol in Stockholm, Sweden, who had 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance. The performance of eGFR cr , eGFR cys , and eGFR cr-cys was assessed against mGFR with median bias, P30 , and correct classification of GFR categories. We stratified analyses within three categories: eGFR cys at least 20% lower than eGFR cr (eGFR cys eGFR cr ). RESULTS: eGFR cr and eGFR cys were similar in 4226 (45%) samples, and among these samples all three estimating equations performed similarly. By contrast, eGFR cr-cys was much more accurate in cases of discordance. For example, when eGFR cys eGFR cr (8% of samples), the median biases were -4.5, 8.4, and 1.4 ml/min per 1.73m 2 . The findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer. CONCLUSIONS: When eGFR cr and eGFR cys are highly discordant in clinical practice, eGFR cr-cys is more accurate than either eGFR cr or eGFR cys .

A Novel Chronic Kidney Disease Phenotyping Algorithm Using Combined Electronic Health Record and Claims Data.

Purpose: Because chronic kidney disease (CKD) is often under-coded as a diagnosis in claims data, we aimed to develop claims-based prediction models for CKD phenotypes determined by laboratory results in electronic health records (EHRs). Patients and Methods: We linked EHR from two networks (used as training and validation cohorts, respectively) with Medicare claims data. The study cohort included individuals ≥65 years with a valid serum creatinine result in the EHR from 2007 to 2017, excluding those with end-stage kidney disease or on dialysis. We used LASSO regression to select among 134 predictors for predicting continuous estimated glomerular filtration rate (eGFR). We assessed the model performance when predicting eGFR categories of <60, <45, <30 mL/min/1.73m2 in terms of area under the receiver operating curves (AUC). Results: The model training cohort included 117,476 patients (mean age 74.8 years, female 58.2%) and the validation cohort included 56,744 patients (mean age 73.8 years, female 59.6%). In the validation cohort, the AUC of the primary model (with 113 predictors and an adjusted R2 of 0.35) for predicting eGFR <60, eGFR<45, and eGFR <30 mL/min/1.73m2 categories was 0.81, 0.88, and 0.92, respectively, and the corresponding positive predictive values for these 3 phenotypes were 0.80 (95% confidence interval: 0.79, 0.81), 0.79 (0.75, 0.84), and 0.38 (0.30, 0.45), respectively. Conclusion: We developed a claims-based model to determine clinical phenotypes of CKD stages defined by eGFR values. Researchers without access to laboratory results can use the model-predicted phenotypes as a proxy clinical endpoint or confounder and to enhance subgroup effect assessment.

Comparing Effectiveness and Safety of SGLT2 Inhibitors vs DPP-4 Inhibitors in Patients With Type 2 Diabetes and Varying Baseline HbA1c Levels.

Importance: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy has been associated with cardiovascular benefits and a few adverse events; however, whether the comparative effectiveness and safety profiles vary with differences in baseline hemoglobin A1c (HbA1c) levels is unknown. Objective: To compare cardiovascular effectiveness and safety of treatment with SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP-4i) in adults with type 2 diabetes (T2D) (1) overall and (2) at varying baseline HbA1c levels. Design, Setting, and Participants: A new-user comparative effectiveness and safety research study was conducted among 144 614 commercially insured adults, initiating treatment with SGLT2i or DPP-4i and with a recorded T2D diagnosis at baseline and at least 1 HbA1c laboratory result recorded within 3 months before treatment initiation. Interventions: The intervention consisted of the initiation of treatment with SGLT2i or DPP-4i. Main Outcomes and Measures: Primary outcomes were a composite of myocardial infarction, stroke, or all-cause death (modified major adverse cardiovascular events [MACE]) and hospitalization for heart failure (HHF). Safety outcomes were hypovolemia, fractures, falls, genital infections, diabetic ketoacidosis (DKA), acute kidney injury (AKI), and lower-limb amputation. Incidence rate (IR) per 1000 person-years, hazard ratios (HR) and rate differences (RD) with their 95% CIs were estimated controlling for 128 covariates. Results: A total of 144 614 eligible adults (mean [SD] age, 62 [12.4] years; 54% male participants) with T2D initiating treatment with a SGLT2i (n = 60 523) or a DPP-4i (n = 84 091) were identified; 44 099 had an HbA1c baseline value of less than 7.5%, 52 986 between 7.5% and 9%, and 47 529 greater than 9%. Overall, 87 274 eligible patients were 1:1 propensity score-matched: 24 052 with HbA1c less than 7.5%; 32 290 with HbA1c between 7.5% and 9%; and 30 932 with HbA1c greater than 9% (to convert percentage of total hemoglobin to proportion of total hemoglobin, multiply by 0.01). The initiation of SGLT2i vs DPP-4i was associated with a reduction in the risk of modified MACE (IR per 1000 person-years 17.13 vs 20.18, respectively; HR, 0.85; 95% CI, 0.75-0.95; RD, -3.02; 95% CI, -5.23 to -0.80) and HHF (IR per 1000 person-years 3.68 vs 8.08, respectively; HR, 0.46; 95% CI, 0.35 to 0.57; RD -4.37; 95% CI, -5.62 to -3.12) over a mean follow-up of 8 months, with no evidence of treatment effect heterogeneity across the HbA1c levels. Treatment with SGLT2i showed an increased risk of genital infections and DKA and a reduced AKI risk compared with DPP-4i. Findings were consistent by HbA1c levels, except for a more pronounced risk of genital infections associated with SGLT2i for HbA1c levels of 7.5% to 9% (IR per 1000 person-years 68.5 vs 22.8, respectively; HR, 3.10; 95% CI, 2.68-3.58; RD, 46.22; 95% CI, 40.54-51.90). Conclusions and Relevance: In this comparative effectiveness and safety research study among adults with T2D, SGLT2i vs DPP-4i treatment initiators had a reduced risk of modified MACE and HHF, an increased risk of genital infections and DKA, and a lower risk of AKI, regardless of baseline HbA1c.

Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with CKD and Type 2 Diabetes: Population-Based US Cohort Study.

BACKGROUND: Limited information exists regarding the safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with CKD treated in routine care. We evaluated the safety of SGLT2i in patients with CKD and type 2 diabetes treated in US routine practice. METHODS: Using claims data from Medicare and two large US commercial databases (April 2013-December 2021), we included 96,128 adults with CKD stages 3-4 and type 2 diabetes who newly filled prescriptions for SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA). Safety outcomes included diabetic ketoacidosis (DKA), lower limb amputations, nonvertebral fractures, genital infections, hypovolemia, AKI, hypoglycemia, and severe urinary tract infections (UTIs). Hazard ratios (HRs) and incidence rate differences per 1000 person-years were estimated after 1:1 propensity score matching, adjusted for >120 baseline characteristics. RESULTS: Compared with GLP-1RA, SGLT2i initiators had a higher risk of nonvertebral fractures (HR, 1.30; 95% confidence interval [CI], 1.03 to 1.65]; incidence rate difference, 2.13 [95% CI, 0.28 to 3.97]), lower limb amputations (HR, 1.65 [95% CI, 1.22 to 2.23]; incidence rate difference, 2.46 [95% CI, 1.00 to 3.92]), and genital infections (HR, 3.08 [95% CI, 2.73 to 3.48]; incidence rate difference, 41.26 [95% CI, 37.06 to 45.46]). Similar risks of DKA (HR, 1.07 [95% CI, 0.74 to 1.54]; incidence rate difference, 0.29 [95% CI, -0.89 to 1.46]), hypovolemia (HR, 0.99 [95% CI, 0.86 to 1.14]; incidence rate difference, 0.20 [95% CI, -2.85 to 3.25]), hypoglycemia (HR, 1.08 [95% CI, 0.92 to 1.26]; incidence rate difference, 1.46 [95% CI, -1.31 to 4.23]), and severe UTI (HR, 1.02 [95% CI, 0.87 to 1.19]; incidence rate difference, 0.35 [95% CI, -2.51 to 3.21]) were observed. SGLT2i had lower risk for AKI (HR, 0.93 [95% CI, 0.87 to 0.99]; incidence rate difference, -6.75 [95% CI, -13.69 to 0.20]). CONCLUSIONS: In US patients with CKD and type 2 diabetes receiving routine care, SGLT2i use was associated with higher risks of genital infections and potentially lower limb amputations and nonvertebral fractures.

Trauma re-engagement and PTSD in older medically ill veterans: implications for trauma-informed care.

OBJECTIVES: We characterize rates and correlates of PTSD and of trauma re-engagement without PTSD in medically ill older Veterans, as well as supportive strategies, with the goal of advancing trauma-informed care. METHODS: We interviewed medically ill older Veterans (N = 88, M age 75.13, SD = 6.14) with primary care screening measures for PTSD and trauma re-engagement, and open-ended questions to assess supportive strategies. RESULTS: One-fifth (20.5%) presented with probable PTSD, associated with greater trauma exposures (r=.57, p<.001), whereas two-fifths (43.2%) reported re-engagement with military memories without PTSD, associated with having a spouse/partner (t = 2.27, p=.028). Of those who experienced trauma, half reported thinking more about the trauma recently and becoming more emotional on certain days. In response to the question 'What gives you strength as you think about the future with your illness' Veterans described support of family, healthcare, worldview, personal control, acceptance, and health behaviors. CONCLUSION: Memories of trauma are common with medical illness. Age-friendly trauma-informed care could consider factors that patients describe as sources of strength with illness.