Hydroxychloroquine lowers Alzheimer's disease and related dementias risk and rescues molecular phenotypes related to Alzheimer's disease.

We recently nominated cytokine signaling through the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83-1.00], 0.87 [0.81-0.93], 0.84 [0.76-0.93], and 0.87 [0.75-1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aß1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.

Risk of fall or fracture with concomitant use of prescription opioids and other medications in osteoarthritis patients.

BACKGROUND: Osteoarthritis (OA) patients taking prescription opioids for pain are at increased risk of fall or fracture, and the concomitant use of interacting drugs may further increase the risk of these events. AIMS: To identify prescription opioid-related medication combinations associated with fall or fracture. MATERIALS & METHODS: We conducted a case-crossover-based screening of two administrative claims databases spanning 2003 through 2021. OA patients were aged 40 years or older with at least 365 days of continuous enrollment and 90 days of continuous prescription opioid use before their first eligible fall or fracture event. The primary analysis quantified the odds ratio (OR) between fall and non-opioid medications dispensed in the 90 days before the fall date after adjustment for prescription opioid dosage and confounding using a case-time-control design. A secondary analogous analysis evaluated medications associated with fracture. The false discovery rate (FDR) was used to account for multiple testing. RESULTS: We identified 41 693 OA patients who experienced a fall and 24 891 OA patients who experienced a fracture after at least 90 days of continuous opioid therapy. Top non-opioid medications by ascending p-value with OR > 1 for fall were meloxicam (OR 1.22, FDR = 0.08), metoprolol (OR 1.06, FDR >0.99), and celecoxib (OR 1.13, FDR > 0.99). Top non-opioid medications for fracture were losartan (OR 1.20, FDR = 0.80), alprazolam (OR 1.14, FDR > 0.99), and duloxetine (OR 1.12, FDR = 0.97). CONCLUSION: Clinicians may seek to monitor patients who are co-prescribed drugs that act on the central nervous system, especially in individuals with OA.

Improving the accuracy of automated gout flare ascertainment using natural language processing of electronic health records and linked Medicare claims data.

BACKGROUND: We aimed to determine whether integrating concepts from the notes from the electronic health record (EHR) data using natural language processing (NLP) could improve the identification of gout flares. METHODS: Using Medicare claims linked with EHR, we selected gout patients who initiated the urate-lowering therapy (ULT). Patients' 12-month baseline period and on-treatment follow-up were segmented into 1-month units. We retrieved EHR notes for months with gout diagnosis codes and processed notes for NLP concepts. We selected a random sample of 500 patients and reviewed each of their notes for the presence of a physician-documented gout flare. Months containing at least 1 note mentioning gout flares were considered months with events. We used 60% of patients to train predictive models with LASSO. We evaluated the models by the area under the curve (AUC) in the validation data and examined positive/negative predictive values (P/NPV). RESULTS: We extracted and labeled 839 months of follow-up (280 with gout flares). The claims-only model selected 20 variables (AUC = 0.69). The NLP concept-only model selected 15 (AUC = 0.69). The combined model selected 32 claims variables and 13 NLP concepts (AUC = 0.73). The claims-only model had a PPV of 0.64 [0.50, 0.77] and an NPV of 0.71 [0.65, 0.76], whereas the combined model had a PPV of 0.76 [0.61, 0.88] and an NPV of 0.71 [0.65, 0.76]. CONCLUSION: Adding NLP concept variables to claims variables resulted in a small improvement in the identification of gout flares. Our data-driven claims-only model and our combined claims/NLP-concept model outperformed existing rule-based claims algorithms reliant on medication use, diagnosis, and procedure codes.

Comparative Safety of Gout Treatment Strategies on Cardiovascular Outcomes Using Observational Data: Clone-censor-weight Target Trial Emulation Approach.

BACKGROUND: We sought to examine the cardiovascular safety of intensive treat-to-target serum urate strategies for gout using Medicare claims data linked to electronic health record laboratory data. METHODS: We selected patients with gout who initiated urate-lowering therapy. We emulated a hypothetical trial comparing the rate of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) among seven different strategies over 24 months. Three aspects were considered in defining increasingly intensive strategies: (1) continuation of urate-lowering therapy, (2) serum urate monitoring, and (3) modification of urate-lowering therapy when serum urate >6 mg/dl. We applied the "clone-censor-weight" method to account for baseline and time-varying confounding. RESULTS: We identified 4402 patients with gout who initiated urate-lowering therapy (mean age 77; male 60%). During a total of 6611 person-years (PY) of follow-up under usual care, the rate of major cardiovascular events (first and recurrent) was 4.5/100 PY (95% CI = 4.0, 5.1). The rate ratios (RRs) suggested reductions (RR point estimates 0.88-0.84) compared with usual care. All 95% CIs were imprecise, but their upper bounds excluded substantial increase in RRs. RRs were closer to 1.0 for the analysis focusing on the first major adverse cardiovascular event during follow-up and on comparison to the strategy requiring continuation of urate-lowering therapy (but not necessarily titration). CONCLUSIONS: Our treatment strategy trial emulation did not find increased risk of major adverse cardiovascular events with intensive urate-lowering strategies. Results may provide reassurance of the cardiovascular safety of intensive treat-to-target serum urate strategies recommended by rheumatology societies.

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.

Risk of malignant melanoma and non-melanoma skin cancer in rheumatoid arthritis patients initiating methotrexate versus hydroxychloroquine: a cohort study.

OBJECTIVES: To characterise the incidence rate of skin cancer associated with methotrexate and hydroxychloroquine in older adults with rheumatoid arthritis (RA). METHODS: RA patients aged ≥65 years who initiated methotrexate or hydroxychloroquine as their first disease modifying antirheumatic drugs (DMARDs). The primary outcome was new occurrence of any skin cancer (i.e. malignant melanoma or non-melanoma skin cancer; NMSC) based on validated algorithms (positive predictive value >83%). Secondary outcomes were malignant melanoma, NMSC, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We estimated the incidence rates (IRs) and hazard ratios (HRs) for each outcome in the 1:1 propensity score (PS)-matched methotrexate and hydroxychloroquine groups. RESULTS: We included 24,577 PS-matched pairs of methotrexate and hydroxychloroquine initiators. Compared with hydroxychloroquine (IR 25.20/1,000 person-years), methotrexate initiators (IR 26.21/1,000 person-years) had a similar risk of any skin cancer [HR 1.03 -(95%CI 0.92, 1.14)] over a mean follow-up of 388 days. The HR (95%CI) associated with methotrexate was 1.39 (0.87, 2.21) for malignant melanoma, 1.01(0.90, 1.12) for NMSC, 1.37 (1.13, 1.66) for BCC, and 0.79 (0.63, 0.99) for SCC compared with hydroxychloroquine. CONCLUSIONS: In this large cohort of older RA patients initiating methotrexate or hydroxychloroquine as their first DMARD, we found no difference in the risk of skin cancer including malignant melanoma and NMSC. However, for specific components of NMSC, methotrexate initiators had higher risk of BCC but lower risk of SCC compared with hydroxychloroquine initiators.

Validation of serostatus of rheumatoid arthritis using ICD-10 codes in administrative claims data.

PURPOSE: To determine the accuracy of International Classification of Diseases- Tenth Revision (ICD-10) diagnosis codes for rheumatoid arthritis (RA) serostatus using a U.S. claims database (Optum Clinformatics Data Mart, Optum) and to compare the results to a previous validation study performed in IBM Marketscan Research Database (sensitivity 73%, positive predictive value, PPV, 84%). METHODS: In Optum (01/01/2016-03/31/2020) linked with laboratory results, we selected RA patients based on ≥2 ICD-10 diagnosis codes for RA (M05 or M06) and at least one dispensing of RA treatments. We included individuals with at least one laboratory result for rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) performed 365 days prior to and including the cohort entry date. An individual was "seropositive" if at least one of the 2 diagnosis codes used to define RA status was M05. "Seronegative" patients were required to have only M06. Secondary analyses were performed using subsets of M05 and M06 diagnosis codes. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa of M05 and M06 against the prespecified reference standard laboratory data. RESULTS: We identified 14 490 adult RA patients who had at least 1 RF or anti-CCP result. The number of patients identified for each reference standard definition ranged from 3315 (reference standard definition: high + anti-CCP) to 13 636 (any + RF). PPV for seropositive RA, M05, was 77.1%. The PPV of M06 for seronegative RA was 61.6%. When we applied more restricted definitions of M05 and M06, the PPV for seropositive RA increased to 79.2%. The PPV for seronegative RA also notably increased to 89.5%. CONCLUSION: ICD-10 codes (M05 and M06) can help identify RA serostatus in claims data, but their limitations should be acknowledged. The PPVs for seropositive and seronegative RA found in the Optum database were lower than those found in MarketScan, perhaps related to database variability or differing patient characteristics and clinical practice. When more restricted definitions of M05 and M06 were used, the PPVs for seropositive and seronegative RA improved to 79.2% and 89.5%, respectively.

Decreased risk of treatment failure with vedolizumab and thiopurines combined compared with vedolizumab monotherapy in Crohn's disease.

OBJECTIVE: While infliximab combined to thiopurines is more effective than infliximab monotherapy in patients with Crohn's disease (CD) and UC, the impact of adding thiopurines to vedolizumab remains controversial. We emulated two target trials comparing the effectiveness of combination therapy versus vedolizumab monotherapy in CD and UC. DESIGN: Based on two US and the French nationwide healthcare databases, patients with CD and UC who initiated vedolizumab were identified. The study methodology, including confounding adjustment and outcome definitions, were previously validated in successful emulations of the SONIC and SUCCESS trials. Risk ratios for treatment failure based on hospitalisation or surgery related to disease activity, treatment switch, or prolonged corticosteroids use, were estimated after 1:1 propensity score (PS) matching. RESULTS: Among a total of 10 299 vedolizumab users, 804 CD and 1088 UC pairs of combination therapy versus vedolizumab monotherapy users were PS matched. Treatment failure occurred at week 26 in 236 (29.3%) and 376 (34.3%) patients with CD and at week 16 in 236 (21.7%) and 263 (24.2%) patients with UC initiating combination therapy and vedolizumab monotherapy, respectively. The risk of treatment failure was decreased with combination therapy compared with vedolizumab monotherapy in CD (RR 0.85, 95% CI: 0.74 to 0.98) and to a lesser extent in UC (RR 0.90, 95% CI: 0.77 to 1.05). Findings were consistent across databases. CONCLUSION: Using validated methodologies, combination therapy with vedolizumab and thiopurines was associated with lower treatment failure compared with vedolizumab monotherapy in CD but not UC across the USA and France.

Risk of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-1RA Therapy.

BACKGROUND: Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits. METHODS: Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013-2018) and were 1:1 propensity score-matched, adjusting for >95 baseline covariates. The primary outcomes were a composite cardiovascular end point (comprising myocardial infarction, stroke, and all-cause mortality) and heart failure hospitalization. Adjusted hazard ratios (HRs) and 95% CIs were estimated in each dataset and pooled through fixed-effects meta-analysis. RESULTS: Among 12 584 propensity score-matched pairs (mean [SD] age, 58.3 [10.9] years; 48.2% male) across the 3 datasets, there were 107 composite cardiovascular end point events (incidence rate per 1000 person-years, 9.9 [95% CI, 8.1-11.9]) among SGLT2i initiators compared with 129 events (incidence rate, 13.0 [95% CI, 10.9-15.3]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.76 (95% CI, 0.59-0.98); this decrease in composite cardiovascular end point was driven by numeric decreases in the risk of myocardial infarction (HR, 0.71 [95% CI, 0.51-1.003]) and all-cause mortality (HR, 0.68 [95% CI, 0.40-1.14]) but not stroke (HR, 1.05 [95% CI, 0.62-1.79]). For the outcome of heart failure hospitalization, there were 141 events (incidence rate, 13.0 [95% CI, 11.0-15.2]) among SGLT2i initiators versus 206 events (incidence rate, 20.8 [95% CI, 18.1-23.8]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.65 (95% CI, 0.50-0.82). CONCLUSIONS: Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of patients with diabetes already on GLP-1RA, addition of SGLT2i conferred greater cardiovascular benefit compared with addition of sulfonylurea. The magnitude of the cardiovascular risk reduction was comparable with the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo, where baseline GLP-1RA use was minimal.

Risk of Serious Infections With Vedolizumab Versus Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The risk of serious infections associated with vedolizumab in patients with inflammatory bowel disease (IBD) is uncertain. We assessed the risk of serious infections associated with use of vedolizumab versus anti-TNF in patients with IBD, according to IBD subtype and previous exposure to anti-TNF. METHODS: Based on two U.S. nationwide commercial insurance databases and the French nationwide health insurance database, anti-TNF naïve and experienced patients diagnosed with Crohn's disease (CD) and ulcerative colitis (UC) aged 18 years or older who initiated vedolizumab or an anti-TNF agent after 2010 were identified. Hazard ratios for serious infections comparing vedolizumab and anti-TNF were estimated in propensity score matched cohorts. RESULTS: Among 8768 vedolizumab and 26,656 anti-TNF initiators included after 1:4 variable ratio propensity score matching, 893 serious infections occurred during 37,725 person-years of follow-up. The risk of serious infections was not different between vedolizumab and anti-TNF in the overall IBD cohort (HR, 0.95; 95% CI, 0·79-1.13), while the risk was decreased for vedolizumab users in patients with UC (HR, 0.68; 95% CI, 0.50-0.93), but not CD (HR, 1.10; 95% CI, 0.87-1.38). In patients with UC, vedolizumab was consistently associated with lower risk of serious infections after exclusion of gastrointestinal infections (HR, 0.59; 95% CI, 0.39-0.90). CONCLUSIONS: While the risk of serious infections associated with vedolizumab was not different compared to anti-TNF in the overall group of patients with IBD, the risk varied according to IBD subtype, by decreasing in patients with UC, but not CD. These findings may help to clarify the optimal position of vedolizumab in the therapeutic management of IBD.

Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study.

OBJECTIVES: Recent results from 'ORAL Surveillance' trial have raised concerns regarding the cardiovascular safety of tofacitinib in patients with rheumatoid arthritis (RA). We further examined this safety concern in the real-world setting. METHODS: We created two cohorts of patients with RA initiating treatment with tofacitinib or tumour necrosis factor inhibitors (TNFI) using deidentified data from Optum Clinformatics (2012-2020), IBM MarketScan (2012-2018) and Medicare (parts A, B and D, 2012-2017) claims databases: (1) A 'real-world evidence (RWE) cohort' consisting of routine care patients and (2) A 'randomised controlled trial (RCT)-duplicate cohort' mimicking inclusion and exclusion criteria of the ORAL surveillance trial to calibrate results against the trial findings. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate HR and 95% CIs for composite outcome of myocardial infarction and stroke and accounting for 76 potential confounders. Database-specific effect estimates were pooled using fixed effects models with inverse-variance weighting. RESULTS: In the RWE cohort, 102 263 patients were identified of whom 12 852 (12.6%) initiated tofacitinib. The pooled weighted HR (95% CI) comparing tofacitinib with TNFI was 1.01 (0.83 to 1.23) in RWE cohort and 1.24 (0.90 to 1.69) in RCT-duplicate cohort which aligned closely with ORAL-surveillance results (HR: 1.33, 95% CI 0.91 to 1.94). CONCLUSIONS: We did not find evidence for an increased risk of cardiovascular outcomes with tofacitinib in patients with RA treated in the real-world setting; however, tofacitinib was associated with an increased risk of cardiovascular outcomes, although statistically non-significant, in patients with RA with cardiovascular risk factors. TRIAL REGISTRATION NUMBER: NCT04772248.

SGLT2 Inhibitors and the Risk of Acute Kidney Injury in Older Adults With Type 2 Diabetes.

RATIONALE & OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to have many benefits for patients with type 2 diabetes. However, whether SGLT2 inhibitors increase the risk of acute kidney injury (AKI) remains unknown. We examined the association of AKI hospitalization with prior initiation of an SGLT2 inhibitor compared with initiation of a dipeptidyl peptidase 4 (DPP-4) inhibitor or a glucagon-like peptide 1 receptor agonist (GLP-1RA) among older adults with type 2 diabetes in routine practice. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: Older adults aged at least 66 years with type 2 diabetes enrolled in Medicare fee-for-service and who were new users of SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1RA agents in the interval from March 2013 to December 2017. EXPOSURES: New use of an SGLT2 inhibitor versus new use of a DPP-4 inhibitor or GLP-1RA. OUTCOME: The primary outcome was hospitalization for AKI, defined as a discharge diagnosis of AKI in the primary or secondary position. ANALYTICAL APPROACH: New users of SGLT2 inhibitors were matched at a 1:1 ratio to new users of DPP-4 inhibitors or GLP-1RAs using propensity scores in 2 pairwise comparisons. Cox proportional hazards regression models generated hazard ratios (HRs) with 95% CIs in propensity score-matched groups. RESULTS: Totals of 68,130 and 71,477 new users of SGLT2 inhibitors were matched to new users of DPP-4 inhibitors or GLP-1RAs, respectively. Overall, the mean age of study participants was 72 years. The risk of AKI was lower in the SGLT2 inhibitor group than in the DPP-4 inhibitor group (HR, 0.71 [95% CI, 0.65-0.76]) or the GLP-1RA group (HR, 0.81 [95% CI, 0.75-0.87]). LIMITATIONS: Residual confounding and lack of laboratory data. CONCLUSIONS: Among older adults with type 2 diabetes, initiation of an SGLT2 inhibitor was associated with a reduced risk of AKI compared with initiation of a DPP-4 inhibitor or a GLP-1RA.

Risk of Hospitalization for Heart Failure in Patients With Hyperkalemia Treated With Sodium Zirconium Cyclosilicate Versus Patiromer.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) and patiromer were recently approved to treat hyperkalemia. Whether the initiation of SZC is associated with an increased risk of hospitalization for heart failure (HHF) compared with patiromer in routine practice remains unknown. METHODS AND RESULTS: We conducted a new-user cohort study of nondialysis adults who initiated SZC or patiromer using Optum's de-identified Clinformatics Data Mart Database from May 2018 to September 2020. We performed propensity score matching in a variable ratio to match each SZC initiator with up to 3 patiromer initiators. The primary outcome was HHF. Cox proportional hazards regression models generated hazard ratios with 95% confidence intervals in the propensity score-matched groups. The cohort included 1126 SZC initiators and 2839 propensity score-matched patiromer initiators. The mean age was 72 years old, approximately 30% had a history of HF, and 85% had chronic kidney disease stages 3-5. The SZC group had 88 cases of HHF (incidence rate 35.8 per 100 person-years), and the patiromer group had 245 cases of HHF (incidence rate 25.1 per 100 person-years). The rate of HHF was numerically higher in the SZC initiators than patiromer initiators (hazard ratio 1.22, 95% confidence interval 0.95-1.56), but did not reach statistical significance. Results were consistent across sensitivity and subgroup analyses. CONCLUSIONS: The initiation of SZC might be associated with an increased risk of HHF compared with patiromer in routine practice. Larger comparative studies are needed to evaluate the safety of SZC in routine practice more precisely.

Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: a meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD). METHODS: We searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke, and cardiovascular death), kidney composite outcomes (a combination of worsening kidney function, end-stage kidney disease, or death from renal or cardiovascular causes), hospitalizations for heart failure (HHF), deaths and safety events (mycotic infections, diabetic ketoacidosis [DKA], volume depletion, amputations, fractures, urinary tract infections [UTI], acute kidney injury [AKI], and hyperkalemia). RESULTS: A total of 26,106 participants with DKD from 8 large-scale trials were included (median age: 65.2 years, 29.7-41.8% women, 53.2-93.2% White, median follow-up: 2.5 years). SGLT2i were associated with reduced risks of MACE (HR 0.83, 95% CI 0.75-0.93), kidney composite outcomes (HR 0.66, 95% CI 0.58-0.75), HHF (HR 0.62, 95% CI 0.55-0.71), cardiovascular death (HR 0.84, 95% CI 0.74-0.96), MI (HR 0.78, 95% CI 0.67-0.92), stroke (HR 0.76, 95% CI 0.59-0.97), and all-cause death (HR 0.86, 95% CI 0.77-0.96), with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73m2). The relative risks (95% CI) for adverse events were 3.89 (1.42-10.62) and 2.50 (1.32-4.72) for mycotic infections in men and women respectively, 3.54 (0.82-15.39) for DKA, and 1.29 (1.13-1.48) for volume depletion. CONCLUSIONS: Among adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.

Secular Trends in the Pharmacologic Treatment of Osteoporosis and Malignancy-Related Bone Disease from 2009 to 2020.

BACKGROUND: New bone-directed therapies, including denosumab, abaloparatide, and romosozumab, emerged during the past decade, and recent trends in use of these therapies are unknown. OBJECTIVE: To examine temporal trends in bone-directed therapies. DESIGN: An open cohort study in a US commercial insurance database, January 2009 to March 2020. PARTICIPANTS/INTERVENTIONS: All-users of bone-directed therapies age >50 years, users with osteoporosis, users with malignancies, and patients with recent (within 180 days) fractures at key osteoporotic sites. MAIN MEASURES: The percentage of each cohort with prescription dispensing or medication administration claims for each bone-directed therapy during each quarter of the study period. KEY RESULTS: We analyzed 15.48 million prescription dispensings or medication administration claims from 1.46 million unique individuals (89% women, mean age 69 years). Among all users of bone-directed therapies, alendronate, and zoledronic acid use increased modestly (49 to 63% and 2 to 4%, respectively, during the study period). In contrast, denosumab use increased rapidly after approval in 2010, overtaking use of all other medications except alendronate by 2017 and reaching 16% of users by March 2020. Similar trends were seen in cohorts of osteoporosis, malignancy, and recent fractures. Importantly, use of any bone-directed therapy after fractures was low and declined from 15 to 8%. CONCLUSIONS: Rates of denosumab use outpaced growth of all other bone-directed therapies over the past decade. Treatment rates after osteoporotic fractures were low and declined over time, highlighting major failings in osteoporosis treatment in the US.

Giant cell arteritis treatment patterns and rates of serious infections.

OBJECTIVES: Giant cell arteritis (GCA) afflicts older adults who may have age- and comorbidity-related risks for infection and is treated with immunosuppressants that increase risk of infection. We examined GCA treatment patterns and rates of serious infections in two real-world cohorts in the U.S. METHODS: We identified two GCA cohorts using two U.S. health insurance databases, Medicare (public, 2007-2017) and MarketScan (commercial, 2015-2019), by applying a validated claims-based algorithm with positive predictive value 79.0% for GCA. We required age ≥50 years and assessed baseline comorbidities, dispensing of immunosuppressants and prophylactic antibiotics, and vaccine administration. We calculated incidence rates (IR) of serious infections, defined as bacterial or viral infections requiring hospitalisation based on primary inpatient diagnosis code. Multivariable Cox proportional hazards models estimated hazard ratios for risk of serious infection for prespecified covariates. RESULTS: The Medicare cohort included 734 patients, 28% male, mean age 77.1; the MarketScan cohort included 1022 patients, 30% male, mean age 68.4. More than 85% used prednisone ≥60mg daily at index date and <10% used tocilizumab. Serious infections developed in 27.9% of Medicare and 7.2% of MarketScan patients: IR per 100 person-years = 10.7 (95% CI 9.3, 12.2) in Medicare and 6.3 (95% CI 5.0, 7.9) in MarketScan. Older age and higher frailty score were significantly associated with increased risk for serious infection. CONCLUSIONS: In these two U.S. GCA cohorts, high-dose glucocorticoids were the most common initial treatment, and over 25% of Medicare and 7% of MarketScan patients developed serious infection during follow-up. Older age and higher frailty score were associated with higher risk of serious infections, though maximum daily prednisone dose was not. Pneumocystis jiroveci pneumonia was rare in two GCA cohorts despite infrequent use of prophylactic antibiotics.

Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy.

PURPOSE: To understand the validity of real-world evidence (RWE) studies in ulcerative colitis (UC), we emulated the SUCCESS randomized controlled trial (RCT) on the effectiveness of infliximab plus thiopurines, using US and French healthcare insurance claims data. METHODS: The SUCCESS trial showed improved remission with infliximab plus thiopurines combined compared to infliximab monotherapy in patients with UC. Based on two US commercial claims databases (IBM MarketScan and Optum) and the French nationwide health insurance database (SNDS) from 2004 through 2019, all patients with UC who initiated combination therapy or infliximab alone were identified. The primary outcome of treatment failure was emulated by: Hospitalization related to UC or colectomy, treatment switch to another biologic or immunosuppressant, or use of corticosteroids 16 weeks after infliximab initiation. We estimated risk ratios with 95% confidence intervals after 1:1 propensity score (PS) matching. RESULTS: Among 620 PS-matched pairs of combination therapy and infliximab monotherapy users, treatment failure occurred in 124 (20%) of patients initiating combination therapy and 170 (27%) during monotherapy. Like in SUCCESS, the risk of treatment failure was decreased with combination therapy in the overall cohort (RR = 0.73; 95% CI: 0.60-0.90). Findings were consistent across MarketScan, Optum, and SNDS: RR = 0.76 (0.57-1.02), 0.82 (0.54-1.24), and 0.61 (0.41-0.90). Similar results were observed for each component endpoint. CONCLUSIONS: RWE results across three large claims databases were consistent with RCT findings. These findings provide support for the use of RWE to assess treatment effectiveness in UC.

Accuracy of identifying diagnosis of moderate to severe chronic kidney disease in administrative claims data.

BACKGROUND: Prior validation studies of claims-based definitions of chronic kidney disease (CKD) using ICD-9 codes reported overall low sensitivity, high specificity, and variable but reasonable PPV. No studies to date have evaluated the accuracy of ICD-10 codes to identify a US patient population with CKD. METHODS: We assessed the accuracy of claims-based algorithms to identify adults with CKD Stages 3-5 compared with laboratory values in a subset (~40%) of a US commercial insurance claims database (Optum's de-identified Clinformatics® Data Mart Database). We calculated the positive predictive value (PPV) of one or two ICD-9 (2012-2014) or ICD-10 (2016-2018) codes for CKD compared with a lab-based estimated glomerular filtration rate (eGFR) occurring within prespecified windows (±90 days, ±180 days, ±365 days) of the ICD-based CKD code(s). RESULTS: The study population ranged between 104 774 and 161 305 patients (ICD-9 cohorts) and between 285 520 and 373 220 patients (ICD-10 cohorts). The mean age was 74.4 years (ICD-9) and 75.6 years (ICD-10) and the median eGFR was 48 ml/min/1.73 m2 . The algorithm of two CKD codes compared with a lab value ±90 days of the first code achieved the highest PPV (PPV 86.36% [ICD-9] and 86.07% [ICD-10]). Overall, ICD-10 based codes had comparable PPVs to ICD-9 based codes and all ICD-10 based algorithms had PPVs >80%. The algorithm of one CKD code compared with laboratory value ±180 days maintained the PPV above 80% but still retained a large number of patients (PPV 80.32% [ICD-9] and 81.56% [ICD-10]). CONCLUSION: An ICD-10-based definition of CKD identified with sufficient accuracy a patient population with CKD Stages 3-5. Our findings suggest that claims databases could be used for future real-world research studies in patients with CKD Stages 3-5.

Sodium-Glucose Cotransporter-2 Inhibitors Versus Glucagon-like Peptide-1 Receptor Agonists and the Risk for Cardiovascular Outcomes in Routine Care Patients With Diabetes Across Categories of Cardiovascular Disease.

BACKGROUND: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in placebo-controlled trials of patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). OBJECTIVE: To evaluate whether SGLT2 inhibitors and GLP-1 RAs are associated with differential cardiovascular benefit among T2D patients with and without CVD. DESIGN: Population-based cohort study. SETTING: Medicare and 2 U.S. commercial claims data sets (April 2013 to December 2017). PARTICIPANTS: 1:1 propensity score-matched adult T2D patients with and without CVD (52 901 and 133 139 matched pairs) initiating SGLT2 inhibitor versus GLP-1 RA therapy. MEASUREMENTS: Primary outcomes were myocardial infarction (MI) or stroke hospitalization and hospitalization for heart failure (HHF). Pooled hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, with 95% CIs, controlling for 138 preexposure covariates. RESULTS: The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with a slightly lower risk for MI or stroke in patients with CVD (HR, 0.90 [95% CI, 0.82 to 0.98]; RD, -2.47 [CI, -4.45 to -0.50]) but similar risk in those without CVD (HR, 1.07 [CI, 0.97 to 1.18]; RD, 0.38 [CI, -0.30 to 1.07]). The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with reductions in HHF risk regardless of baseline CVD in patients with CVD (HR, 0.71 [CI, 0.64 to 0.79]; RD, -4.97 [CI, -6.55 to -3.39]) and in those without CVD (HR, 0.69 [CI, 0.56 to 0.85]; RD, -0.58 [CI, -0.91 to -0.25]). LIMITATION: Treatment selection was not randomized. CONCLUSION: Use of SGLT2 inhibitors versus GLP-1 RAs was associated with consistent reductions in HHF risk among T2D patients with and without CVD, although the absolute benefit was greater in patients with CVD. There were no large differences in risk for MI or stroke among T2D patients with and without CVD. PRIMARY FUNDING SOURCE: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.

Cardiovascular risk associated with allopurinol vs. benzbromarone in patients with gout.

AIMS: With the high prevalence of gout and associated cardiovascular (CV) diseases, information on the comparative CV safety of individual urate-lowering drugs becomes increasingly important. However, few studies examined the CV risk of uricosuric agents. We compared CV risk among patients with gout who initiated allopurinol vs. benzbromarone. METHODS AND RESULTS: Using the Korean National Health Insurance claims data (2002-17), we conducted a cohort study of 124 434 gout patients who initiated either allopurinol (n = 103 695) or benzbromarone (n = 20 739), matched on propensity score at a 5:1 ratio. The primary outcome was a composite CV endpoint of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. To account for competing risk of death, we used cause-specific hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes comparing allopurinol initiators with benzbromarone. Over a mean follow-up of 1.16 years, 2258 patients developed a composite CV event. The incidence rate of the composite CV event was higher in allopurinol initiators (1.81 per 100 person-years) than benzbromarone (1.61 per 100 person-years) with a HR of 1.22 (95% CI 1.05-1.41). The HR for all-cause mortality was 1.66 (95% CI 1.43-1.93) among allopurinol initiators compared with benzbromarone. CONCLUSION: In this large population-based cohort of gout patients, allopurinol was associated with an increased risk of composite CV events and all-cause mortality compared to benzbromarone. Benzbromarone may reduce CV risk and mortality in patients with gout, although more studies are necessary to confirm our findings and to advance our understanding of the underlying mechanisms.