McCoy, Rozalina G.

Objective The aim of this study was to compare infection‐related hospitalization risk among patients with nonrenal systemic lupus erythematosus initiating commonly used immunosuppressants. Methods We emulated a target trial using Optum Labs Data Warehouse claims to compare the risk of infection‐related hospitalization among patients initiating azathioprine, belimumab, methotrexate, or mycophenolic acid analogues (MPAAs) between March 2011 and September 2023. We excluded patients with prior lupus nephritis, solid‐organ or bone marrow transplantation, or rituximab/cyclophosphamide exposure. The primary outcome was time to first infection‐related hospitalization using intention‐to‐treat (ITT) and per‐protocol (PP) analyses. We applied inverse probability of treatment weighting to account for baseline covariates and fitted marginal structural Cox models incorporating time‐varying monthly glucocorticoid dose during follow‐up. Results Among 6,168 patients, 24‐month cumulative incidence of infection‐related hospitalization was 10% (95% confidence interval [CI] 8–12) for azathioprine, 8% (95% CI 5–10) for belimumab, 10% (95% CI 8–11) for methotrexate, and 13% (95% CI 10–15) for MPAAs. In ITT analyses, MPAAs had higher risk than belimumab (hazard ratio [HR] 1.55, 95% CI 1.07–2.25) and methotrexate (HR 1.32, 95% CI 1.04–1.68). In PP analyses, azathioprine (HR 2.04, 95% CI 1.01–4.16) and MPAAs (HR 2.27, 95% CI 1.11–4.62) had higher risk compared with belimumab. After accounting for time‐varying monthly glucocorticoid dose, between‐treatment differences were no longer significant. Conclusion Initial differences in the infection‐related hospitalization risk were attenuated after accounting for time‐varying glucocorticoid exposure. These findings highlight glucocorticoid exposure as an important factor associated with serious infection risk while recognizing that postbaseline glucocorticoid use may reflect both evolving disease activity and a pathway through which therapies influence infection risk. image

OBJECTIVE Severe (level 3) hypoglycemia is a life-threatening complication of diabetes associated with substantial risk of recurrence and long-term morbidity. This study examined how adults with diabetes interpreted severe hypoglycemic events and why they declined participation in a community paramedicine program (Diabetes Rescue, Engagement, and Management [Diabetes-REM]) designed to prevent recurrence. RESEARCH DESIGN AND METHODS We conducted semistructured qualitative interviews with adults with type 1 or type 2 diabetes who experienced severe hypoglycemia requiring emergency medical services and declined enrollment in Diabetes-REM. Interviews explored hypoglycemia management experiences and reasons for nonparticipation and were explored using thematic analysis. RESULTS Sixteen adults (44% female; mean age 60 years, range 25–83) participated. Four interrelated themes emerged. First, participants normalized glucose variability as a baseline condition of diabetes and interpreted severe events as situational and correctable when a cause was identifiable, or as inevitable when it was not, rather than as evidence of increased risk. Second, participants relied on prevention systems encompassing habitual routines, caregiver involvement, and glucose-monitoring technologies. Third, severe episodes were frightening and disruptive but typically prompted adjustments to personal management over pursuit of additional clinical support. Finally, reasons for declining Diabetes-REM included time constraints (56%), perceived lack of benefit (25%), and privacy concerns or discomfort with home visits (25%). CONCLUSIONS Among adults who declined a community paramedicine hypoglycemia prevention intervention, severe events were absorbed into existing self-management frameworks rather than viewed as signals of increased risk. Programs targeting hypoglycemia recurrence should account for patients’ risk perceptions and existing management systems, positioning support as complementary rather than corrective.

OBJECTIVE To examine kidney disease outcomes associated with dipeptidyl peptidase 4 inhibitors (DPP-4i). RESEARCH DESIGN AND METHODS In this target trial emulation, claims data from enrollees in commercial, Medicare Advantage, and traditional Medicare health plans were used to identify adults ≥21 years old with type 2 diabetes, with moderate cardiovascular risk, and without stage 3 or worse chronic kidney disease (CKD) initiating alogliptin, linagliptin, saxagliptin, or sitagliptin between 2014 and 2021. The primary outcome was a composite of incident CKD stages 3–5, kidney failure, or kidney replacement therapy. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method and incorporated as inverse probability of treatment weights into proportional hazards models. RESULTS The weighted study cohort included 3,026 individuals starting alogliptin, 38,213 starting linagliptin, 14,934 starting saxagliptin, and 115,091 starting sitagliptin. One year after treatment initiation, the primary outcome occurred in 1.4%, 2.7%, 2.2%, and 2.4% of patients initiating alogliptin, linagliptin, saxagliptin, and sitagliptin, respectively, increasing to 3.2%, 6.2%, 5.0%, and 5.4%, respectively, at 3 years. Alogliptin was associated with lower risk of stage 3 or worse CKD than linagliptin (hazard ratio [HR] 0.50; 95% CI 0.37–0.69), saxagliptin (HR 0.63; 95% CI 0.45–0.86), and sitagliptin (HR 0.58; 95% CI 0.42–0.79), while saxagliptin was associated with lower risk than linagliptin (HR 0.80; 95% CI 0.73–0.87). Conversely, linagliptin was associated with higher risk than sitagliptin (HR 1.15, 95% CI 1.10–1.21). CONCLUSIONS Alogliptin was associated with lower risk of moderate-to-severe kidney disease than other DPP-4i, while linagliptin was associated with higher risk. Limitations include lack of laboratory data and potential unmeasured confounding.

Introduction To assess the within-class variation in kidney outcomes following initiation of sulfonylurea therapy. Research design and methods We used claims data of enrollees in commercial, Medicare Advantage, and traditional Medicare health plans between 2014 and 2021 to emulate a target trial including adults ≥21 years with type 2 diabetes at moderate cardiovascular risk to compare initiation of glimepiride, glipizide, or glyburide on the incidence of chronic kidney disease (CKD) stage 3 or worse, including initiation of kidney replacement therapy (primary outcome); secondary outcomes examined incident CKD stages 3-4, kidney failure (including kidney replacement therapy), all-cause mortality, and hypoglycemia requiring emergency department or hospital care. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method, and incorporated as inverse probability of treatment weights into proportional hazards models. Results The weighted study cohort included 295 092 individuals starting glimepiride (n=134 926), glipizide (n=145 984), and glyburide (n=14 182). One year after treatment initiation, stage 3 or worse CKD developed in 2.1% of patients in the glimepiride group, 2.2% in the glipizide group, and 1.8% in the glyburide group. Glyburide was associated with a lower risk of kidney complications compared with both glimepiride (HR 0.84, 95% CI 0.76 to 0.92) and glipizide (HR 0.81, 95% CI 0.73 to 0.89), despite a higher risk of severe hypoglycemia (HR 1.47, 95% CI 1.27 to 1.71 vs glipizide and HR 1.22, 95% CI 1.05 to 1.42 vs glimepiride). In contrast, the risk of kidney complications was modestly increased with glipizide compared with glimepiride use (HR 1.04, 95% CI 1.00 to 1.07). Conclusions Glyburide was associated with a modestly lower risk of kidney complications, despite a higher risk of hypoglycemia, while glipizide was associated with a higher risk of kidney complications. These hypothesis-generating findings suggest important within-class differences that warrant consideration in clinical decision-making and future research. Despite rigorous prespecified causal inference analytic methods, the risk of unmeasured confounding and bias by indication with the use of observational data remains. Trial registration number NCT05214573 .

Background SGLT2 (sodium‐glucose cotransporter 2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetes. However, no direct comparison of individual SGLT2 inhibitor drugs has been conducted, particularly among adults with moderate cardiovascular risk who comprise most people with type 2 diabetes. Methods We used data for commercial, Medicare Advantage, and Medicare fee‐for‐service beneficiaries to emulate a target trial of adults (≥21 years) with type 2 diabetes and moderate cardiovascular risk who started canagliflozin, dapagliflozin, or empagliflozin between 2015 and 2020. We estimated propensity scores using the super learner ensemble method and incorporated them as inverse probability of treatment weights into Cox models, estimating risk of MACE, expanded MACE, and hyperglycemic and hypoglycemic crises through December 31, 2022. Results The weighted cohort, balanced on all baseline covariates, included 137 232 patients (mean age 65.7 years [SD, 8.1], 75.3% non‐Hispanic White, 57.0% male, 81.9% on metformin, 11.4% on glucagon‐like peptide‐1 receptor agonists) starting canagliflozin (N=42 877), dapagliflozin (N=17 871), or empagliflozin (N=7648). The risk of MACE was lower among patients starting empagliflozin versus canagliflozin (hazard ratio [HR], 0.92 [95% CI, 0.87–0.97]), driven by reduced risk of all‐cause mortality (HR, 0.86 [95% CI, 0.80–0.94]). There was no difference in MACE between empagliflozin versus dapagliflozin or dapagliflozin versus canagliflozin therapy. There was no difference in remaining outcomes between the three drugs. Conclusions The 3 most used SGLT2 inhibitor medications demonstrate similar effectiveness on cardiovascular outcomes among patients with type 2 diabetes at moderate cardiovascular risk, with differences between these drugs small in magnitude. Clinicians and health systems should prioritize enhancing access to these cardioprotective therapies.

ABSTRACT Sodium glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are nephroprotective and their use is recommended for adults with chronic kidney disease (CKD). The role of SGLT2i and GLP‐1 RAs in patients with acute kidney injury (AKI) is unknown. This systematic review aimed to estimate the effect of SGLT2i or GLP‐1 RAs on clinical outcomes in AKI. We systematically searched Embase, MEDLINE, Scopus, Web of Science Core Collection, and clinical trials registries for observational studies and clinical trials from database inception to July 3, 2025. Included studies evaluated adults (≥ 18 years) with AKI during a hospitalization and compared patients subsequently exposed to either SGLT2i or GLP‐1 RAs to a non‐exposed control group. Random effects meta‐analyses were performed. Six studies related to SGLT2i (five observational, one randomized trial) and one related to GLP‐1 RAs (one observational) met eligibility criteria ( N = 432,048 patients). SGLT2i/GLP‐1 RA exposure was associated with lower odds of major adverse kidney events (MAKE) (OR 0.63, 95% CI 0.46–0.86) and all‐cause mortality [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.21–0.62] compared to controls. The odds for kidney replacement therapy were lower with SGLT2i therapy in the three studies where it was evaluated (OR 0.61, 95% CI 0.40–0.93). Sensitivity analyses restricted to SGLT2i data were consistent with the overall findings [MAKE OR 0.63 (95% CI 0.42–0.95); Mortality OR 0.34 (95% CI 0.18, 0.65)]. Exposure to SGLT2i or GLP‐1 RAs after AKI, examined primarily in observational studies, was associated with improved clinical outcomes. These findings are promising and warrant evaluation in randomized clinical trials.

Abstract Context Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity and can lead to substantial weight loss. In patients taking levothyroxine, weight loss can reduce thyroid hormone requirements and potentially associated adverse effects. Thyroid-stimulating hormone (TSH) monitoring is essential but unclear whether thyroid function is routinely reassessed after GLP-1 RAs initiation. Objective Examine the changes in the timing of TSH testing after GLP-1 RAs. Design Retrospective cohort study emulating a target trial using Medicare from January 1, 2011, to December 31, 2020. The primary analysis followed an intention-to-treat approach. Patients were matched 1:1 using propensity scores. Logistic regression models and informed by least absolute shrinkage operator variable selection were used. Setting The 15% sample of U.S. Medicare fee-for-service claims data. Patients or Other Participants Adults aged ≥65 years with type 2 diabetes on a stable levothyroxine dose at baseline. Intervention(s) Initiation of GLP-1 RAs vs initiation/ongoing use of sodium-glucose cotransporter-2 inhibitors (SGLT-2is). Main Outcome Measure(s) TSH testing during follow-up. Results Among 5370 matched patients, the mean age was 73.2 years. 71.6% were women, and 87.1% were White. Approximately 83.0% of patients in both treatment groups receive a TSH testing within a 1-year follow-up. The mean time to TSH testing was approximately 130.5 days for both groups. Conclusion TSH testing patterns did not differ between GLP-1 RAs and SGLT-2is, despite the greater likelihood of requiring levothyroxine dose adjustment associated with weight loss seen with GLP-1 RA therapy. Given levothyroxine's widespread use, this gap suggests missed opportunities for timely and weight-responsive thyroid monitoring.

Abstract Context Osteoanabolic therapy for osteoporosis should be followed by antiresorptive treatment (“consolidation”) to preserve bone mass. Although osteoanabolic therapy is increasingly endorsed for primary fracture prevention, real-world implementation of consolidation remains unknown. Objective To assess patterns and predictors of timely consolidation after osteoanabolic therapy for primary fracture prevention. Methods We conducted a retrospective cohort study using US commercial, Medicare Advantage, and traditional Medicare claims data. Adults aged ≥50 years who initiated romosozumab, teriparatide, or abaloparatide between 2011 and 2022 were included. The primary outcome was timely consolidation, defined as initiation of an antiresorptive medication within 3 months after osteoanabolic therapy. Secondary outcomes included delayed consolidation (initiation >3 months after completion), osteoanabolic restart following a treatment gap, and no consolidation therapy. We further distinguished participants who completed the full osteoanabolic course, defined as ≥12 months for romosozumab and ≥18 months for teriparatide or abaloparatide. Multivariable logistic regression models were used to identify predictors of consolidation patterns. Results Among 15 389 patients (mean age 70.6 years; 89% women; 85% White), 30% completed osteoanabolic therapy (median, 12.9 months for romosozumab; 23.4 months for teriparatide/abaloparatide). Overall, 25% had timely consolidation, 24% delayed consolidation, 12% restarted osteoanabolics, and 40% had no consolidation; only 12% completed therapy with timely consolidation. Timely consolidation was more likely with endocrinology (OR 1.31; 95% CI, 1.17-1.48) or rheumatology (OR 1.45; 1.30-1.62) vs primary care, and less likely among patients aged 50-64 years (OR 0.67; 0.58-0.77) vs 65-74, those enrolled in Medicare Advantage (OR 0.85; 0.74-0.98) vs traditional Medicare, or those recently hospitalized (OR 0.88; 0.80-0.97). Odds increased over time (OR 4.27; 3.63-5.05 for 2021 vs 2011 starts). Conclusion Only 1 in 4 patients received timely consolidation therapy after osteoanabolic treatment, and 1 in 8 completed the full sequence. Strategies to improve consolidation in primary fracture prevention are needed.