Prevalence and Risk Factors of Post-Acute Sequela of COVID-19 in Adults with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: Incidence and manifestations of post-acute sequelae of COVID-19 (PASC) are poorly defined among immunosuppressed populations. We reported, phenotyped, and assessed risk factors for PASC in adults with systemic autoimmune diseases. METHODS: Persons ≥18 years with systemic autoimmune diseases were recruited into a national, prospective cohort of SARS-CoV-2 vaccination between 12/2020-4/2021. Serial surveys assessed vaccination status, SARS-CoV-2 infection incidence, and disease flares. Participants reporting SARS-CoV-2 infection received a questionnaire assessing symptom duration, severity, and quality of life (QoL) impact; PASC was defined as ≥1 symptom persisting for >12 weeks. PASC syndromes were mapped via overlapping symptom domains. Characteristics were compared between participants who did versus did not report PASC. RESULTS: Among 1615 participants, 590 (36.5%) reported SARS-CoV-2 infection and were sent PASC surveys, 299 (50.7%) of whom responded >12 weeks following reported infection. Respondents were 1.62% female, 90.2% white, median (IQR) age 48(40-60) years with median (IQR) 3 (2-3) vaccine doses at time of first infection. Common diagnoses included inflammatory arthritis (38.5%) and inflammatory bowel disease (14.4%). 89/299 (29.8%) reported PASC, with the most reported symptom domain being neurological/psychological (83.1%); 84% reported an impact on QoL. Participants with PASC reported lower number of preceding vaccines (median [IQR] 2[2-3] versus 3[2-3]; p<0.001) and more reinfections (16.9% versus 5.7%; p=0.004). CONCLUSION: 29.8% of persons with systemic autoimmune disease in a large real-world cohort reported PASC, often affecting QoL. Preceding vaccination may reduce PASC, whereas multiple infections may increase risk, supporting ongoing booster vaccine campaigns and efforts to limit breakthrough infections.

A protocol for scoping reviews on the role of whole-body and dedicated body-part magnetic resonance imaging for assessment of adult and juvenile idiopathic inflammatory myopathies.

Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.

Brepocitinib, a potent and selective TYK2/JAK1 inhibitor: scientific and clinical rationale for dermatomyositis.

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/ß, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

Bariatric surgery and all-cause mortality: A methodological review of studies using a non-surgical comparator.

AIM: Non-randomized studies on bariatric surgery have reported large reductions in mortality within 6-12 months after surgery compared with non-surgical patients. It is unclear whether these findings are the result of bias. STUDY DESIGN AND SETTING: We searched PubMed to identify all non-randomized studies investigating the effect of bariatric surgery on all-cause mortality compared with non-surgical patients. We assessed these studies for potential confounding and time-related biases. We conducted bias analyses to quantify the effect of these biases. RESULTS: We identified 21 cohort studies that met our inclusion criteria. Among those, 11 were affected by immortal time bias resulting from the misclassification or exclusion of relevant follow-up time. Five studies were subject to potential confounding bias because of a lack of adjustment for body mass index (BMI). All studies used an inadequate comparator group that lacked indications for bariatric surgery. Bias analyses to correct for potential confounding from BMI shifted the effect estimates towards the null [reported hazard ratio (HR): 0.78 vs. bias-adjusted HR: 0.92]. Bias analyses to correct for the presence of immortal time also shifted the effect estimates towards the null (adjustment for 2-year wait time: reported HR: 0.57 vs. bias-adjusted HR: 0.81). CONCLUSION: Several important sources of bias were identified in non-randomized studies of the effectiveness of bariatric surgery versus non-surgical comparators on mortality. Future studies should ensure that confounding by BMI is accounted for, considering the choice of the comparator group, and that the design or analysis avoids immortal time bias from the misclassification or exclusion.

SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: population based cohort study.

OBJECTIVES: To evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in routine clinical practice. DESIGN: Population based cohort study with active-comparator, new user design. SETTING: Claims data from Medicare and two large commercial insurance databases in the United States from April 2013 to April 2022. PARTICIPANTS: 1:1 propensity score matched adults with type 2 diabetes newly starting SGLT-2 inhibitors versus DPP-4 inhibitors (n=778 908), GLP-1 receptor agonists versus DPP-4 inhibitors (n=729 820), and SGLT-2 inhibitors versus GLP-1 receptor agonists (n=873 460). MAIN OUTCOME MEASURES: Hyperkalemia diagnosis in the inpatient or outpatient setting. Secondary outcomes were hyperkalemia defined as serum potassium levels ≥5.5 mmol/L and hyperkalemia diagnosis in the inpatient or emergency department setting. RESULTS: Starting SGLT-2 inhibitor treatment was associated with a lower rate of hyperkalemia than DPP-4 inhibitor treatment (hazard ratio 0.75, 95% confidence interval (CI) 0.73 to 0.78) and a slight reduction in rate compared with GLP-1 receptor agonists (0.92, 0.89 to 0.95). Use of GLP-1 receptor agonists was associated with a lower rate of hyperkalemia than DPP-4 inhibitors (0.79, 0.77 to 0.82). The three year absolute risk was 2.4% (95% CI 2.1% to 2.7%) lower for SGLT-2 inhibitors than DPP-4 inhibitors (4.6% v 7.0%), 1.8% (1.4% to 2.1%) lower for GLP-1 receptor agonists than DPP-4 inhibitors (5.7% v 7.5%), and 1.2% (0.9% to 1.5%) lower for SGLT-2 inhibitors than GLP-1 receptor agonists (4.7% v 6.0%). Findings were consistent for the secondary outcomes and among subgroups defined by age, sex, race, medical conditions, other drug use, and hemoglobin A1c levels on the relative scale. Benefits for SGLT-2 inhibitors and GLP-1 receptor agonists on the absolute scale were largest for those with heart failure, chronic kidney disease, or those using mineralocorticoid receptor antagonists. Compared with DPP-4 inhibitors, the lower rate of hyperkalemia was consistently observed across individual agents in the SGLT-2 inhibitor (canagliflozin, dapagliflozin, empagliflozin) and GLP-1 receptor agonist (dulaglutide, exenatide, liraglutide, semaglutide) classes. CONCLUSIONS: In people with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of hyperkalemia than DPP-4 inhibitors in the overall population and across relevant subgroups. The consistency of associations among individual agents in the SGLT-2 inhibitor and GLP-1 receptor agonist classes suggests a class effect. These ancillary benefits of SGLT-2 inhibitors and GLP-1 receptor agonists further support their use in people with type 2 diabetes, especially in those at risk of hyperkalemia.

Health Care Utilization and Costs Associated With Empagliflozin in Older Adults With Type 2 Diabetes.

OBJECTIVE: We compared health care resource utilization (HCRU) and costs for inpatient and outpatient services and dispensed medications in older adults with type 2 diabetes initiating empagliflozin versus dipeptidyl peptidase 4 inhibitors (DPP-4is). RESEARCH DESIGN AND METHODS: The study population included U.S. Medicare fee-for-service beneficiaries with diabetes (age ≥65 years) initiating empagliflozin or DPP-4is (August 2014 to September 2018). We estimated rate ratios (RRs) for HCRU outcomes using zero-inflated negative binomial regression and per-member per-year (PMPY) cost differences using generalized linear model with gamma distributions, overall and stratified by baseline cardiovascular disease (CVD), after adjusting for 143 baseline covariates using 1:1 propensity score matching. RESULTS: We identified 23,335 matched pairs (mean age 72 years, 51% with baseline CVD). HCRU rates were lower in empagliflozin versus DPP-4i initiators (number of inpatient days, RR 0.89 [95% CI 0.82, 0.97]; number of emergency department [ED] visits, 0.86 [0.82, 0.91]; number of hospitalizations, 0.86 [0.79, 0.93]; number of office visits, 0.96 [0.95, 0.98]). Inpatient cost (-$713 PMPY [95% CI -847, -579), outpatient cost (-$198 PMPY[-272, -124]), and total cost of care (-$1,109 PMPY [-1,478, -739]) were lower for empagliflozin versus DPP-4is, although diabetes medication cost was higher in empagliflozin initiators ($454 PMPY [95% CI 284, 567]). In the CVD subgroup, total cost was lower for empagliflozin initiators (-$2,005 PMPY [-2,451, -1,337]), while the difference was attenuated in the non-CVD subgroup (-$296 PMPY[-740, 148]). CONCLUSIONS: Among older adults with diabetes, empagliflozin was associated with a lower number of inpatient days, hospitalizations, ED visits, and office visits and with lower costs of care compared with DPP-4is, especially in those with history of CVD.

The Impact of Radiation Therapy in Patients with Systemic Sclerosis and Head and Neck Cancer.

OBJECTIVE: Systemic sclerosis (SSc) is considered a relative, or in some cases, absolute contraindication for radiation therapy for various cancers; however, radiation is the standard of care and the best option for tumor control for locally advanced head and neck (H&N) cancer. We present a case series to document postradiation outcomes in patients with SSc and H&N cancer. METHODS: Patients with SSc and H&N cancer treated with radiation were identified from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center research registries. Through chart review, we identified whether patients developed predetermined acute and late side effects or changes in SSc activity from radiation. We further describe therapies used to prevent and treat radiation-induced fibrosis. RESULTS: Thirteen patients with SSc who received radiation therapy for H&N cancer were included. Five-year survival was 54%. Nine patients (69%) developed local radiation-induced skin thickening, and 7 (54%) developed reduced neck range of motion. Two patients required long-term percutaneous endoscopic gastrostomy use due to radiation therapy complications. No patients required respiratory support related to radiation therapy. Regarding SSc disease activity among the patients with established SSc before radiation therapy, none experienced interstitial lung disease progression in the postradiation period. After radiation, one patient had worsening skin disease outside the radiation field; however, this patient was within the first year of SSc, when progressive skin disease is expected. Treatment strategies to prevent radiation fibrosis included pentoxifylline, amifostine, and vitamin E, while intravenous immunoglobulin (IVIG) was used to treat it. CONCLUSION: Although some patients with SSc who received radiation for H&N cancer developed localized skin thickening and reduced neck range of motion, systemic flares of SSc were uncommon. This observational study provides evidence to support the use of radiation therapy for H&N cancer in patients with SSc when radiation is the best treatment option.

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.

Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

Myositis mimics in scleroderma: A case series of neuromuscular diseases that can co-exist in scleroderma.

We present a case series of four patients with systemic sclerosis and skeletal myopathy. While idiopathic inflammatory myopathies, or myositis, are thought to be the most common type of muscle disease seen in systemic sclerosis, we highlight four cases where unique clinical findings and careful assessment ruled out myositis mimics. Key diagnostic tools that can be helpful for clinicians to diagnose a neuromuscular disease are also detailed in this report.

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.

Current myositis clinical trials and tribulations.

With improved understanding of disease pathogenesis and availability of outcome measures, there has been a remarkable increase in the number of therapeutic clinical trials in idiopathic inflammatory myopathies (myositis) over the last three years reaching as many as five trials per site. These trials share similar design and inclusion/exclusion criteria resulting in a competitive clinical trial landscape in myositis. While these are exciting times for the myositis field, we have a number of concerns about the design and conduct of the myositis trials. These include competitive landscape, lengthy placebo arms, underrepresentation of minority groups among participants, use of patient reported outcome measures with limited/no data on validity in myositis, antiquated disease classification criteria, and unclear performance of the ACR/EULAR Myositis Response Criteria in skin-predominant patients despite inclusion of these patients in trials. In this viewpoint, we further discuss these concerns and offer potential solutions such as including patient perspectives in the trial design and adoption of innovative frameworks.

Idiopathic inflammatory myopathies: current insights and future frontiers.

Idiopathic inflammatory myopathies are a group of autoimmune diseases with a broad spectrum of clinical presentations, primarily characterised by immune-mediated muscle injury. Until recently, there was little insight into the pathogenesis of idiopathic inflammatory myopathies, which challenged the recognition of the breadth of heterogeneity of this group of diseases as well as the development of new therapeutics. However, the landscape of idiopathic inflammatory myopathies is evolving. In the past decade, advances in diagnostic tools have facilitated an enhanced understanding of the underlying disease mechanisms in idiopathic inflammatory myopathies, enabling the expansion of therapeutic trials. The fields of transcriptomics, prot§eomics, and machine learning offer the potential to gain greater insights into the underlying pathophysiology of idiopathic inflammatory myopathies. Harnessing insights gained from these sophisticated tools could contribute to the identification of differences at a molecular level among patients, accelerating the development of targeted, tailored therapies. Bolstered by the validation and standardisation of robust outcome measures, many promising therapies are in clinical trial development. Although challenges remain, there is great optimism in the field due to the progress in innovative diagnostics, outcome measures, and therapeutic approaches. In this Review, we discuss the expanding landscape of idiopathic inflammatory myopathies as the frontier of precision medicine becomes imminent.

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.

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.