Positive Control Outcomes Research Articles

Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes

Sclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25–85% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors.

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for recurrent nephrolithiasis among patients with pre-existing nephrolithiasis or gout: target trial emulation studies.

To emulate target trials comparing recurrence of nephrolithiasis among patients with pre-existing nephrolithiasis (overall and stratified by concomitant gout) initiating sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus an active comparator. Target trial emulation studies. Canadian population database, January 2014 to June 2022. 20 146 patients with nephrolithiasis and type 2 diabetes, including those with concomitant gout at baseline, a high risk group. Initiation of an SGLT-2 inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist, with a dipeptidyl peptidase-4 (DPP-4) inhibitor as alternative comparator. The primary outcome was recurrent nephrolithiasis events ascertained from diagnoses during emergency department visits, hospital admissions, or outpatient visits. Secondary outcomes included nephrolithiasis resulting in hospital admission or emergency department visits and flare-up of gout, as well as a positive control outcome (genital infection) and negative control outcomes (osteoarthritis encounter and appendicitis). Poisson and Cox proportional hazards regression models were used (primary analyses), as well as overlap weighting. After inverse probability of treatment weighting, 1924 recurrent nephrolithiasis events occurred among the 14 456 weighted patients who used an SGLT-2 inhibitor (105.3 per 1000 person years), compared with 853 events among the 5877 weighted patients who used a GLP-1 receptor agonist (156.4 per 1000 person years). The adjusted rate ratio was 0.67 (95% confidence interval (CI) 0.57 to 0.79) and rate difference was -51 (95% CI -63 to -40) per 1000 person years, with a number needed to treat (NNT) of 20. Among those with recently active nephrolithiasis, the absolute rate difference was 219 per 1000 person years (NNT of 5). Protective associations persisted for nephrolithiasis events that required emergency department visits, hospital admissions, or procedures, and when an SGLT-2 inhibitor was compared with a DPP-4 inhibitor (rate ratio 0.73 (0.68 to 0.78), rate difference -38 (-46 to -29) per 1000 person years (NNT of 26)). Protective associations also persisted among patients with nephrolithiasis and concomitant gout, with a rate ratio of 0.67 (0.57 to 0.79) and rate difference of -53 (95% CI -78 to -27) per 1000 person years versus a GLP-1 receptor agonist (NNT of 19), and 0.63 (0.55 to 0.72) and-62 (-81 to -42) per 1000 person years, respectively, versus a DPP-4 inhibitor (NNT of 16). Furthermore, SGLT-2 inhibitor use was associated with a lower rate of gout flare-ups (rate ratio 0.72, 0.54 to 0.95, rate difference -16, -31 to -1 per 1000 person years) compared with GLP-1 receptor agonists (0.65, 0.52 to 0.82, and -21, -33 to -9 per 1000 person years) compared with DPP-4 inhibitors. SGLT-2 inhibitor initiators showed higher risk of genital infection (eg, hazard ratio 2.21, 95% CI 1.68 to 2.90, and rate difference 13 per 1000 person years), but no altered risk of osteoarthritis encounter (0.87, 0.68 to 1.1, and -2 per 1000 person years) or appendicitis (1.07, 0.69 to 1.67, and 1 per 1000 person years). Results were similar when propensity score overlap weighting was applied. The benefits associated with SGLT-2 inhibitor for patients with nephrolithiasis in these target trial emulations suggest they may be a useful addition to current treatments to simultaneously manage nephrolithiasis recurrence and comorbidities, including gout.

Risk of Suicidal Ideation or Attempts in Adolescents With Obesity Treated With GLP1 Receptor Agonists

Glucagon-like peptide 1 receptor agonists (GLP1R) are increasingly being used for the treatment of obesity in adolescents. It is currently unknown whether GLP1R treatment is associated with suicidal ideation or attempts in this population. To investigate the association between GLP1R initiation and suicidal ideation or attempts in adolescents with obesity. Retrospective propensity score-matched cohort study using electronic health records from the TriNetX global federated network between December 2019 and June 2024. The analysis included data from 120 health care organizations, mainly from the USA. Participants were adolescents aged 12 to 18 years with a diagnosis of obesity and evidence of an antiobesity GLP1R prescription or lifestyle intervention without GLP1R within the following year. Cohorts were balanced for baseline demographic characteristics, psychiatric medications and comorbidities, and diagnoses associated with socioeconomic status and health care access using propensity score matching. Initial prescription of GLP1R (study cohort) or lifestyle intervention without GLP1R (control cohort). Incidence of suicidal ideation or attempts based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded in patient electronic health records during 12 months of follow-up. Diagnoses of upper respiratory tract infections (URTI) were used as negative control outcomes, and gastrointestinal symptoms (GI) were used as positive control outcomes. A total of 4052 adolescents with obesity and a concomitant antiobesity intervention were identified for the GLP1R cohort and 50 112 were identified for the control cohort. Propensity score matching resulted in 3456 participants in each balanced cohort. Prescription of GLP1R was associated with a 33% reduced risk for suicidal ideation or attempts over 12 months of follow-up (1.45% vs 2.26%; hazard ratio [HR], 0.67; 95% CI, 0.47-0.95; P = .02) and a higher rate of GI symptoms (6.9% vs 5.4%; HR, 1.41; 95% CI, 1.12-1.78; P = .003) but no difference in rates of URTI diagnoses. In this study, adolescents with obesity prescribed a GLP1R had a lower incidence of suicidal ideation or attempts compared with matched patients not prescribed GLP1R who were treated with lifestyle intervention. These results suggest a favorable psychiatric safety profile of GLP1R in adolescents. The detected reduction in HRs for suicidal ideation among adolescents with obesity prescribed GLP1R suggests potential avenues for future research.

Target Trial Emulation Using Cohort Studies: Estimating the Effect of Antihypertensive Medication Initiation on Incident Dementia.

Observational studies link high midlife systolic blood pressure to increased dementia risk. However, the synthesis of evidence from randomized controlled trials has not definitively demonstrated that antihypertensive medication use reduces dementia risk. Here, we emulate target trials of antihypertensive medication initiation on incident dementia using three cohort studies, with attention to potential violations of necessary assumptions. We emulated trials of antihypertensive medication initiation on incident dementia using data from the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, and Health and Retirement Study. We used data-driven methods to restrict participants to initiators and noninitiators with overlap in propensity scores and positive control outcomes to look for violations of positivity and exchangeability assumptions. Analyses were limited by the small number of cohort participants who met eligibility criteria. Associations between antihypertensive medication initiation and incident dementia were inconsistent and imprecise (Atherosclerosis Risk in Communities: HR = 0.30 [0.05, 1.93]; Cardiovascular Health Study: HR = 0.66 [0.27, 1.64]; Health and Retirement Study: HR = 1.09 [0.75, 1.59]). More stringent propensity score restrictions had little effect on findings. Sensitivity analyses using a positive control outcome unexpectedly suggested antihypertensive medication initiation increased the risk of coronary heart disease in all three samples. Positive control outcome analyses suggested substantial residual confounding in effect estimates from our target trials, precluding conclusions about the impact of antihypertensive medication initiation on dementia risk through target trial emulation. Formalized processes for identifying violations of necessary assumptions will strengthen confidence in target trial emulation and avoid inappropriate confidence in emulated trial results.

Genetically Proxied Antidiabetic Drug Target and Primary Open-Angle Glaucoma: A Mendelian Randomization Study.

Observational studies suggest that antidiabetic drugs may lower POAG risk; while the causal relationship remains unclear. Naturally occurring variation in genes encoding antidiabetics drug targets can be used as proxies to investigate long-term therapeutic effect of these drugs on POAG risk. We performed a two-sample Mendelian randomization study to evaluate the potential effect of antidiabetic drug targets on POAG in Europeans and East Asians. To proxy antidiabetic drugs (ABCC8, PPARG, GLP1R, SLC5A2), we leveraged genetic variants located near or within drug target genes that were associated with HbA1c. The validity of our ancestry-specific genetic instrument was checked with multipul positive control outcomes. Genetic summary statistics of POAG from the International Glaucoma Genetics Consortium, Global Biobank Meta-analysis Initiative, and FinnGen consortia were analyzed for Europeans (38,164 cases and 1,576,179 controls) and East Asians (16,650 cases and 288,833 controls) separately. Inverse-variance weighted random-effects models were used as primary method. MR results provided consistent evidence of a protective effect of ABCC8 inhibition on POAG using data sets from IGG, GBMI, and FinnGen. Genetically predicted one-standard deviation reduction in HbA1c from ABCC8 inhibition were significant associated with lower risk of POAG in Europeans (OR = 0.211, 95% CI: 0.133-0.333; p < 0.001) and East Asians (OR = 0.070, 95% CI: 0.011-0.459; p = 0.0056). The association between genetically predicted ABCC8 inhibition and risk of POAG was mainly mediated through intraocular pressure. No association was found for PPARG, SLC5A2, or GLP1R. Sensitivity analyses supported this observation. We found a protective effect of genetically proxied ABCC8 inhibition on POAG risk in both Europeans and East Asians, highlighting ABCC8 as a promising candidate drug target for POAG, and mechanisms underlying the protective effect should also be investigated.

Can Breastfeeding Prevent Long-Term Overweight and Obesity in Children? A Population-Based Cohort Study.

The aims of this study were to assess the impact of exclusive breastfeeding up to 6 months of age on reducing the incidence of overweight and obesity in children up to 10 years of age and to estimate the annual incidence of obesity and overweight in the study population. Our retrospective cohort analysis using electronic health records included children from zero to ten years old, born between 1 January 2006 and 31 December 2022, followed up at the Unidade Local de Saúde de Matosinhos (ULSM). Information on their comorbidity history was collected, and positive or negative control results were defined. In the first year of life, around 29% of the children on exclusive breastfeeding were obese and 20% were overweight. This trend was reversed by the age of 9. Asthma and allergic rhinitis were used as positive control outcomes and allergic dermatitis as a negative control outcome. There seems to be no relationship between exclusive and non-exclusive breastfeeding and the development of overweight or obesity at the age of 10. The results showed that breastfeeding is associated with a lower risk of asthma in the future.

#1704 GLP-1RA versus DPP-4 inhibitors and rates of hyperkalemia and discontinuation of renin-angiotensin system (RAS) blockade in Swedish routine care

Abstract Background and Aims Emerging evidence suggest that glucagon-like peptide-1 receptor agonists (GLP-1RA) influence tubular handling of electrolytes and increase potassium excretion, which may translate into reduced risk of hyperkalemia. Hyperkalemia is a common complication that limits persistence on guideline-recommended RAS inhibitors (RASi). Here, we quantified and compared rates of hyperkalemia and RASi discontinuation among users of GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in a large healthcare system. Method We used data from the SCREAM project (Jan 2008-Dec 2021) to conduct a population-based active-comparator, new-user cohort study of adults with type-2 diabetes who started GLP-1RA or DPP-4i. The primary outcome was hyperkalemia occurrence, overall (plasma potassium&amp;gt;5.0 mmol/L) and by severity (mild -potassium &amp;gt;5-≤5.5 mmol/L- and moderate-severe -potassium &amp;gt;5.5 mmol/L- hyperkalemia). Among ongoing RASi users, we assessed time to RASi discontinuation through evaluation of subsequent RASi dispensations. Cox regression with inverse probability of treatment weighting (IPTW) was used to estimate pooled hazard ratios (HRs) and rate differences. Major cardiovascular events (MACEs) served as positive control outcome to evaluate unmeasured confounding bias. Results During a median follow-up of 3.0 (Interquartile range [IQR] 1.2-5.6) years, we identified 33 280 eligible participants, of which 13 633 started GLP-1RA and 19 647 DPP-4i. Mean age was 64 years and 40% were women. Compared with DPP-4i, starting GLP-1RA was associated with a lower rate of hyperkalemia (Hazard ratio [HR] 0.91; 95% CI: 0.84-0.99, Fig. 1), with no suggestion of effect modification by baseline eGFR strata (HR 0.91 (0.78-1.07) for eGFR ≥60 and HR 0.92 (0.83-1.01) for eGFR &amp;lt;60 ml/min/1.73 m2, P for interaction &amp;gt;0.05). Similar findings were observed for mild (HR 0.90; 0.83-0.98) and moderate-severe (HR 0.92; 0.80-1.06) hyperkalemia. Out of 21 751 participants that were using RASi, 8 463 discontinued this therapy during median 2.0 (0.7, 4.1) years of follow-up. Initiation of GLP-1RA vs. DPP-4i was associated with lower rate of RASi discontinuation (HR: 0.93; 0.87-0.98), with no interaction across strata of baseline eGFR (HR 0.97 (0.83-1.12) for eGFR ≥60 and HR 0.93 (0.87-0.99) for &amp;lt;60 ml/min/1.73 m2, P for interaction &amp;gt;0.05). Consistent with trial evidence, we observed a lower rate of MACE for GLP-1RA vs DPP-4i (HR 0.87; 0.78-0.98). Conclusion In patients with diabetes managed in routine care, the use of GLP-1RA was associated with lower rates of hyperkalemia and discontinuation of RASi compared with DPP-4i, providing further observational evidence in support of the use of these medications.

Causal relationship between genetic proxies for calcium channel blockers and the risk of depression: a drug-target Mendelian randomization study.

Calcium channel blockers (CCBs) are widely used in the clinical management of hypertension. Depression, a common comorbidity of hypertension, is an important issue in the management of hypertension. However, the impact of CCBs on depression risk remains controversial. We aim to investigate the causal effect of CCBs on depression through drug-target Mendelian randomization (MR) analysis. To proxy CCBs, we utilized the genetic variations located in or around drug target genes that were related to systolic blood pressure (SBP). Coronary artery disease (CAD) served as the positive control outcome. Genetic summary data of SBP, CAD, and depression were obtained from genome-wide association studies (GWAS) based on European population. Inverse variance weighted (IVW) method was applied as the main analysis to estimate the causal effect. Cochran's Q test, MR-Egger intercept, MR pleiotropy residual sum and outlier (MR-PRESSO) and leave-one-out sensitivity analysis were used to test the robustness of the results. Meta-analysis was applied to further confirm whether causal relationships existed between CCBs and depression. The IVW results failed to reveal any causal relationship between genetic proxies for CCBs and depression (P > 0.05). Cochran's Q test showed no evidence of heterogeneity (P > 0.05). The MR-Egger intercept test suggested no evidence of directional pleiotropy, and the MR pleiotropy residual sum and outlier (MR-PRESSO) global test for horizontal pleiotropy was also not significant (P > 0.05). Leave-one-out analysis did not reveal any genetic variant that influenced the results. In addition, the meta-analysis further confirmed the absence of a causal relationship. The present study indicates no association of genetic proxies for CCBs with depression. Further studies are necessary to provide definitive evidence.

Non-linear Mendelian randomization: detection of biases using negative controls with a focus on BMI, Vitamin D and LDL cholesterol

Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the “residual” exposure). These “local” causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method—the doubly-ranked method—has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects—that of low-density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest there should be extensive simulation and empirical methodological examination of performance of both methods for NLMR under different conditions before further use of these methods. In the interim, use of NLMR methods needs justification, and a number of sanity checks (such as analysis of negative and positive control outcomes, sensitivity analyses excluding removal of strata at the extremes of the distribution, examination of biological plausibility and triangulation of results) should be performed.

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits. To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy. This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022. Initiation of SGLT2i vs sulfonylurea. The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023. Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting. In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

Causal effects from inflammatory bowel disease on liver function and disease: a two-sample Mendelian randomization study.

Accumulating evidence has shown that patients with inflammatory bowel disease (IBD) have liver function abnormalities and are susceptible to liver diseases. However, the existence of a causal relationship between IBD and liver function or disease remains unclear. A two-sample Mendelian randomization (MR) analysis was performed using genetic associations from publicly available genome-wide association studies (GWAS). These associations encompass ulcerative colitis (UC), Crohn's disease (CD), liver function traits, and liver disease phenotypes. The liver function traits comprised hepatic biochemistries, percent liver fat, and liver iron content from the UK Biobank. Furthermore, the liver disease phenotypes included cholelithiasis, non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC) in cohorts of European ancestry. The primary estimation used the inverse-variance weighted method, with GWAS of C-reactive protein (CRP) in the UK Biobank serving as a positive control outcome. Genetically predicted UC is causally associated with decreased levels of albumin (ALB) and liver iron content, while genetically predicted CD is causally associated with increased levels of alkaline phosphatase (ALP). Moreover, genetically predicted UC or CD increases the risk of PSC, and CD increases the risk of PBC. Neither UC nor CD causally increases the risk of cholelithiasis and NAFLD. UC affects the levels of ALB and liver iron content, while CD affects the levels of ALP. Both UC and CD increase the risk of PSC, and CD increases the risk of PBC.

Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study

BackgroundWith increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics.MethodsA drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong’s “Children of 1997” birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the “Children of 1997” birth cohort and coronary artery disease from Biobank Japan.ResultsGenetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], − 1.06 [− 1.52 to − 0.60]; PCSK9: − 0.93 [− 1.56 to − 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid − 0.79 [− 1.25 to − 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed.ConclusionsStatins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.

Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study

BackgroundEffectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) on preventing progressive chronic kidney outcomes is uncertain for type 2 diabetes (T2D) patients requiring intensive glycemic control. This study aimed to evaluate comparative effectiveness of GLP-1RA versus LAI therapies on progressive chronic kidney outcomes among patients having poor glycemic control and requiring these injectable glucose-lowering agents (GLAs).Methods7279 propensity-score-matched pairs of newly stable GLP-1RA and LAI users in 2013–2018 were identified from Taiwan’s National Health Insurance Research Database and followed until death or 12/31/2019 (intention-to-treat). Subdistributional hazard model was utilized to assess the comparative effectiveness on a composite renal outcome (i.e., renal insufficiency [eGFR < 15 mL/min/1.73 m2], dialysis-dependent end-stage renal disease [ESRD], or renal death) and its individual components. Sensitivity analyses with the as-treated scenario, PS weighting, high-dimensional PS techniques, using cardiovascular diseases (CVDs) as positive control outcomes, and interaction testing were performed.ResultsIn primary analyses, subdistribution hazard ratios (95% CIs) for initiating GLP-1RAs versus LAIs for the composite renal outcome, renal insufficiency, dialysis-dependent ESRD, and renal death were 0.39 (0.30–0.51), 0.43 (0.32–0.57), 0.29 (0.20–0.43), and 0.28 (0.15–0.51), respectively. Sensitivity analysis results were consistent with the primary findings. CVD history and the medication possession ratio of prior oral GLAs possessed modification effects on GLP-1RA-associated kidney outcomes.ConclusionUsing GLP-1RAs versus LAIs was associated with kidney benefits in T2D patients requiring intensive glycemic control and potentially at high risk of kidney progression. GLP-1RAs should be prioritized to patients with CVDs or adherence to prior oral GLAs to maximize kidney benefits.

The Association of Class I and II Human Leukocyte Antigen Serotypes With End-Stage Kidney Disease Due to Membranoproliferative Glomerulonephritis and Dense Deposit Disease

Membranoproliferative glomerulonephritis (MPGN), encompassing several distinct diseases, is a rare but significant cause of kidney failure in the United States. The potential etiologies of MPGN are unclear, but prior studies have suggested dysregulation of the alternative complement pathway and, recently, autoimmunity as potential mechanisms driving MPGN pathogenesis. In this study, we examined HLA associations with end-stage kidney disease (ESKD) due to MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse US-based cohort. Case-control study. Using US Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) data, we identified 3,424 patients with kidney failure due to MPGN and 263 due to DDD. We matched patients to kidney donor controls on designated race and ethnicity in a 1:15 ratio. 58 class I and II HLA serotypes. Case-control status. For each disease cohort, univariable and multivariable logistic regression analyses were used to investigate associations between the disease and 58 HLA serotypes. In subgroup analyses, we investigated HLA associations in White and Black patients. We also studied antiglomerular basement membrane (anti-GBM) nephritis as a positive-control outcome. We applied a Bonferroni correction to account for multiple comparisons. Eighteen serotypes were significantly associated with the odds of having MPGN in univariable analyses, with DR17 having the strongest association (odds ratio [OR], 1.55 [95% CI, 1.44-1.68], P=4.33e-28). No significant associations were found between any HLA serotype and DDD. Designated race-specific analyses showed comparable findings. We recapitulated known HLA associations in anti-GBM nephritis. Reliance on HLA serotypes (rather than genotype), lack of biopsy-confirmed diagnoses. HLA-DR17 is associated with ESKD due to MPGN in a racially and ethnically diverse cohort. The strength of association was similar in White and Black patients, suggesting a role in the pathogenesis of MPGN. No HLA associations were observed in patients with DDD. Prior studies have suggested dysregulation of the alternative complement pathway as a potential etiology of membranoproliferative glomerulonephritis (MPGN), but recent evidence from a British White population has implicated an autoimmune mechanism in MPGN pathogenesis. We investigated HLA associations between MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse cohort of patients. We found that HLA-DR17 is associated with end-stage kidney disease (ESKD) due to MPGN in both White and Black patients. By contrast, no significant HLA associations with ESKD due to DDD were identified. These results suggest a role for autoimmunity in some cases of MPGN and highlight differences in the disease etiology of MPGN compared with DDD.

No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study.

To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. A cross-sectional analysis of baseline and prospectively collected cohort data. UK Biobank (UKBB) participants of genetically determined European ancestry (n= 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n= 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n= 1970), and the Blue Mountains Eye Study (BMES; n= 2440). Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93-0.99; P= 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96-0.99; P= 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87-0.97; P= 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08-1.54; P < 0.01) and cataract (OR, 1.15; 1.04-1.28; P= 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89-1.19; P= 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84-1.12; P= 0.65). A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Serially Combining Epidemiological Designs Does Not Improve Overall Signal Detection in Vaccine Safety Surveillance.

Vaccine safety surveillance commonly includes a serial testing approach with a sensitive method for 'signal generation' and specific method for 'signal validation.' The extent to which serial testing in real-world studies improves or hinders overall performance in terms of sensitivity and specificity remains unknown. We assessed the overall performance of serial testing using three administrative claims and one electronic health record database. We compared type I and II errors before and after empirical calibration for historical comparator, self-controlled case series (SCCS), and the serial combination of those designs against six vaccine exposure groups with 93 negative control and 279 imputed positive control outcomes. The historical comparator design mostly had fewer type II errors than SCCS. SCCS had fewer type I errors than the historical comparator. Before empirical calibration, the serial combination increased specificity and decreased sensitivity. Type II errors mostly exceeded 50%. After empirical calibration, type I errors returned to nominal; sensitivity was lowest when the methods were combined. While serial combination produced fewer false-positive signals compared with the most specific method, it generated more false-negative signals compared with the most sensitive method. Using a historical comparator design followed by an SCCS analysis yielded decreased sensitivity in evaluating safety signals relative to a one-stage SCCS approach. While the current use of serial testing in vaccine surveillance may provide a practical paradigm for signal identification and triage, single epidemiological designs should be explored as valuable approaches to detecting signals.

OA15 IL-13 inhibition used for atopic diseases is associated with risk of psoriatic arthritis

Abstract Background/Aims Inhibitors of the IL-13 pathway, such as dupilumab and tralokinumab, are licensed to treat atopic diseases such as eczema and asthma. Musculoskeletal adverse events that resemble enthesitis and psoriatic arthritis (PsA) after dupilumab initiation have been reported, but evidence is limited to case reports and spontaneous pharmacovigilance with uncertain causal inference. Naturally occurring genetic variation in drug targets can provide insight into their potential adverse effects. We used population-level data to investigate whether genetically proxied IL-13 inhibition (IL-13i) increases risk of PsA and other spondyloarthritis-related diseases. Methods Dupilumab is recognised to reduce eosinophil count in clinical studies; we therefore used it as the biomarker of IL-13i. We instrumented IL-13i using missense (protein coding) variants within the IL13 gene that are associated with circulating eosinophil count at genome-wide significance (p &amp;lt; 5x10-8) in a study of 563,946 individuals. Outcome genetic associations were taken from studies of PsA, psoriasis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis and iritis. To examine instrument validity, we used atopic eczema and asthma as positive control outcomes, and rheumatoid arthritis as a negative control. We used the ratio method, with estimates scaled to per standard deviation (SD ∼0.14x109/L) reduction in eosinophil count. Results One missense variant, rs20541, was selected to proxy IL-13i. Genetically proxied IL-13i was associated with increased risk of PsA (OR 37.39; 95%CI 11.52, 121.34), psoriasis (OR 20.08; 4.38, 92.01), Crohn’s disease (OR 3.49; 1.38, 8.81), but not ulcerative colitis, ankylosing spondylitis or iritis. IL-13i was associated with reduced risk of positive control outcomes, but not with the negative control (Table 1). Conclusion Genetically proxied IL-13 inhibition is associated with increased risk of PsA, psoriasis and Crohn’s disease, which may be a class effect relevant to other IL-13i that are not yet reported to have Th17-type adverse events. These findings are compatible with the hypothesis that Th2 cytokines IL-4/-13 may act as a restraint toward Th17-type disease activation in some organs. Clinicians assessing adverse events after dupilumab initiation should be aware of incident PsA and related features. This study demonstrates the value of MR in evaluating rare adverse events in the study of drug safety. Disclosure S. Zhao: None. K.L. Hyrich: None. Z.Z.N. Yiu: None. A. Barton: None. J. Bowes: None.

Hypothetical intervention of targeted systolic blood pressure control of &lt; 120 mmHg on renal prognosis for persons with stage 3–4 chronic kidney disease: an application of parametric g-formula using health checkup data in Japan

The revised KDIGO guidelines recommend maintaining systolic blood pressure (sBP) < 120mmHg in patients with chronic kidney disease (CKD), based on cardiovascular and survival benefits. However, the renal benefit of this strategy remains less clear. We used data of routine health checkups in Japan. Persons whose estimated glomerular filtration rate (eGFR) was < 60mL/min/1.73 m2 in 2015 without end-stage disease were followed until 2020. We estimated the 5-year benefit of hypothetical targeted sBP control using parametric g-formula modeling, accounting for both time-fixed and time-varying confounding variables. Four sensitivity analyses, including analysis using a marginal structural model (MSM) and positive control outcome analysis, were also done. We enrolled 28,972 persons with CKD (median age: 54years, male: 69%, baseline eGFR [median]: 56mL/min/1.73m2). As compared with the natural course without a targeted intervention, there was no renoprotective effect of targeted sBP control, with a 5-year difference in eGFR of 0.65mL/min/1.73 m2 (95% confidence interval - 0.42 to 1.65mL/min/1.73 m2). MSM analysis found a similar result. In contrast, the positive control analysis using the cardiovascular outcome showed that targeted sBP control would reduce the cardiovascular disease incidence by 6.0% over 5years. A targeted sBP control strategy maintaining < 120mmHg may not yield a renoprotective effect for patients with stage 3-4 CKD, although it was expected to offer a cardiovascular benefit. Future research may be warranted in higher-risk populations, such as elderly people or those with more advanced kidney disease.

Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion.

Carotid stenosis is thought to be the primary risk factor for central retinal artery occlusion (CRAO); however, it is not known whether atrial fibrillation (AF)-a cardiac arrhythmia that underlies over 25% of cerebral ischemic strokes-predisposes patients to CRAO. A retrospective, observational, cohort study was performed using data from the State Inpatient Databases and State Emergency Department Databases from New York (2006-2015), California (2003-2011), and Florida (2005-2015) to determine the association between AF and CRAO. The primary exposure was hospital-documented AF. The primary end point was hospital-documented CRAO, defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification, code 362.31 in the primary diagnosis position. Cause-specific hazard models were used to model CRAO-free survival among patients according to hospital-documented AF status. Of 39 834 885 patients included in the study, 2 723 842 (median age, 72.7 years; 48.5% women) had AF documented during the exposure window. The median follow-up duration was 6 years and 1 month. Patients with AF were older, more likely to be of non-Hispanic White race/ethnicity, and had a higher burden of cardiovascular comorbidities compared with patients without AF. The cumulative incidence of CRAO determined prospectively after exclusions was 8.69 per 100 000 at risk in those with AF and 2.39 per 100 000 at risk in those without AF over the study period. Before adjustment, AF was associated with higher risk of CRAO (hazard ratio, 2.55 [95% CI, 2.15-3.03]). However, after adjustment for demographics, state, and cardiovascular comorbidities, there was an inverse association between AF and risk of CRAO (adjusted hazard ratio, 0.72 [95% CI, 0.60-0.87]). These findings were robust in our prespecified sensitivity analyses. By contrast, positive control outcomes of embolic and ischemic stroke showed an expected strong relationship between AF and risk of stroke. We found an inverse association between AF and CRAO in a large, representative study of hospitalized patients; however, this cohort did not ascertain AF or CRAO occurring outside of hospital or emergency department settings.

Associations of Genetically Predicted Vitamin B12 Status across the Phenome.

Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20-0.50) and pernicious anaemia (0.29, 0.19-0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated.