High-dimensional characterization of post-acute sequelae of COVID-19.

The acute clinical manifestations of COVID-19 have been well characterized1,2, but the post-acute sequelae of this disease have not been comprehensively described. Here we use the national healthcare databases of the US Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequelae-including diagnoses, medication use and laboratory abnormalities-in patients with COVID-19 who survived for at least 30 days after diagnosis. We show that beyond the first 30 days of illness, people with COVID-19 exhibit a higher risk of death and use of health resources. Our high-dimensional approach identifies incident sequelae in the respiratory system, as well as several other sequelae that include nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anaemia. We show increased incident use of several therapeutic agents-including pain medications (opioids and non-opioids) as well as antidepressant, anxiolytic, antihypertensive and oral hypoglycaemic agents-as well as evidence of laboratory abnormalities in several organ systems. Our analysis of an array of prespecified outcomes reveals a risk gradient that increases according to the severity of the acute COVID-19 infection (that is, whether patients were not hospitalized, hospitalized or admitted to intensive care). Our findings show that a substantial burden of health loss that spans pulmonary and several extrapulmonary organ systems is experienced by patients who survive after the acute phase of COVID-19. These results will help to inform health system planning and the development of multidisciplinary care strategies to reduce chronic health loss among individuals with COVID-19.

Acute Pancreatitis Recurrences Augment Long-Term Pancreatic Cancer Risk.

INTRODUCTION: In animal models, inflammation caused by experimental acute pancreatitis (AP) promotes pancreatic carcinogenesis that is preventable by suppressing inflammation. Recent studies noted higher long-term risk of pancreatic ductal adenocarcinoma (PDAC) after AP. In this study, we evaluated whether the long-term PDAC risk after AP was influenced by the etiology of AP, number of recurrences, and if it was because of progression to chronic pancreatitis (CP). METHODS: This retrospective study used nationwide Veterans Administration database spanning 1999-2015. A 2-year washout period was applied to exclude patients with preexisting AP and PDAC. PDAC risk was estimated in patients with AP without (AP group) and with underlying CP (APCP group) and those with CP alone (CP group) and compared with PDAC risk in patients in a control group, respectively, using cause-specific hazards model. RESULTS: The final cohort comprised 7,147,859 subjects (AP-35,550 and PDAC-16,475). The cumulative PDAC risk 3-10 years after AP was higher than in controls (0.61% vs 0.18%), adjusted hazard ratio (1.7 [1.4-2.0], P < 0.001). Adjusted hazard ratio was 1.5 in AP group, 2.4 in the CP group, and 3.3 in APCP group. PDAC risk increased with the number of AP episodes. Elevated PDAC risk after AP was not influenced by the etiology of AP (gallstones, smoking, or alcohol). DISCUSSION: There is a higher PDAC risk 3-10 years after AP irrespective of the etiology of AP, increases with the number of episodes of AP and is additive to higher PDAC risk because of CP.

Kidney Outcomes in Long COVID.

BACKGROUND: COVID-19 is associated with increased risk of post-acute sequelae involving pulmonary and extrapulmonary organ systems-referred to as long COVID. However, a detailed assessment of kidney outcomes in long COVID is not yet available. METHODS: We built a cohort of 1,726,683 US Veterans identified from March 1, 2020 to March 15, 2021, including 89,216 patients who were 30-day survivors of COVID-19 and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE). MAKE was defined as eGFR decline ≥50%, ESKD, or all-cause mortality. We used inverse probability-weighted survival regression, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates, including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory. RESULTS: Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR, 1.94; 95% CI, 1.86 to 2.04), eGFR decline ≥30% (aHR, 1.25; 95% CI, 1.14 to 1.37), eGFR decline ≥40% (aHR, 1.44; 95% CI, 1.37 to 1.51), eGFR decline ≥50% (aHR, 1.62; 95% CI, 1.51 to 1.74), ESKD (aHR, 2.96; 95% CI, 2.49 to 3.51), and MAKE (aHR, 1.66; 95% CI, 1.58 to 1.74). Increase in risks of post-acute kidney outcomes was graded according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared with non-infected controls, 30-day survivors of COVID-19 exhibited excess eGFR decline (95% CI) of -3.26 (-3.58 to -2.94), -5.20 (-6.24 to -4.16), and -7.69 (-8.27 to -7.12) ml/min per 1.73 m2 per year, respectively, in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection. CONCLUSIONS: Patients who survived COVID-19 exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should include attention to kidney disease.

Particulate Matter Air Pollution and the Risk of Incident CKD and Progression to ESRD.

Elevated levels of fine particulate matter <2.5 µm in aerodynamic diameter (PM2.5) are associated with increased risk of cardiovascular outcomes and death, but their association with risk of CKD and ESRD is unknown. We linked the Environmental Protection Agency and the Department of Veterans Affairs databases to build an observational cohort of 2,482,737 United States veterans, and used survival models to evaluate the association of PM2.5 concentrations and risk of incident eGFR <60 ml/min per 1.73 m2, incident CKD, eGFR decline ≥30%, and ESRD over a median follow-up of 8.52 years. County-level exposure was defined at baseline as the annual average PM2.5 concentrations in 2004, and separately as time-varying where it was updated annually and as cohort participants moved. In analyses of baseline exposure (median, 11.8 [interquartile range, 10.1-13.7] µg/m3), a 10-µg/m3 increase in PM2.5 concentration was associated with increased risk of eGFR<60 ml/min per 1.73 m2 (hazard ratio [HR], 1.21; 95% confidence interval [95% CI], 1.14 to 1.29), CKD (HR, 1.27; 95% CI, 1.17 to 1.38), eGFR decline ≥30% (HR, 1.28; 95% CI, 1.18 to 1.39), and ESRD (HR, 1.26; 95% CI, 1.17 to 1.35). In time-varying analyses, a 10-µg/m3 increase in PM2.5 concentration was associated with similarly increased risk of eGFR<60 ml/min per 1.73 m2, CKD, eGFR decline ≥30%, and ESRD. Spline analyses showed a linear relationship between PM2.5 concentrations and risk of kidney outcomes. Exposure estimates derived from National Aeronautics and Space Administration satellite data yielded consistent results. Our findings demonstrate a significant association between exposure to PM2.5 and risk of incident CKD, eGFR decline, and ESRD.

Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus.

Experimental evidence suggests that higher levels of urea may increase insulin resistance and suppress insulin secretion. However, whether higher levels of blood urea nitrogen (BUN) are associated with increased risk of incident diabetes mellitus in humans is not known. To study this, we built a national cohort of 1,337,452 United States Veterans without diabetes to characterize the association of BUN and risk of incident diabetes. Over a median follow-up of 4.93 years, there were 172,913 cases of incident diabetes. In joint risk models of estimated glomerular filtration rate (eGFR) and BUN. there was no association between eGFR and the risk of incident diabetes in those with a BUN of 25 mg/dl or less. However, the risk was significantly increased in those with a BUN over 25 mg/dl at all eGFR levels, even in those with an eGFR of 60 ml/min/1.73m2 or more (hazard ratio 1.27; confidence interval 1.24-1.31). The risk of incident diabetes was highest in those with BUN over 25 mg/dL and an eGFR under 15 ml/min/1.73m2 (1.68; 1.51-1.87). Spline analyses of the relationship between BUN and risk of incident diabetes showed that risk was progressively higher as BUN increased. In models where eGFR was included as a continuous covariate, compared to a BUN of 25 mg/dl or less, a BUN over 25 mg/dl was associated with increased risk of incident diabetes (1.23; 1.21-1.25). Every 10 ml/min/1.73m2 decrease in eGFR was not associated with risk of incident diabetes (1.00; 1.00-1.01). Two-stage residual inclusion analyses showed that, independent of the impact of eGFR, every 10 mg/dL increase in BUN concentration was associated with increased risk of incident diabetes (1.15; 1.14-1.16). Thus, higher levels of BUN are associated with increased risk of incident diabetes mellitus.

Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.

The last quarter century witnessed significant population growth, aging, and major changes in epidemiologic trends, which may have shaped the state of chronic kidney disease (CKD) epidemiology. Here, we used the Global Burden of Disease study data and methodologies to describe the change in burden of CKD from 1990 to 2016 involving incidence, prevalence, death, and disability-adjusted-life-years (DALYs). Globally, the incidence of CKD increased by 89% to 21,328,972 (uncertainty interval 19,100,079- 23,599,380), prevalence increased by 87% to 275,929,799 (uncertainty interval 252,442,316-300,414,224), death due to CKD increased by 98% to 1,186,561 (uncertainty interval 1,150,743-1,236,564), and DALYs increased by 62% to 35,032,384 (uncertainty interval 32,622,073-37,954,350). Measures of burden varied substantially by level of development and geography. Decomposition analyses showed that the increase in CKD DALYs was driven by population growth and aging. Globally and in most Global Burden of Disease study regions, age-standardized DALY rates decreased, except in High-income North America, Central Latin America, Oceania, Southern Sub-Saharan Africa, and Central Asia, where the increased burden of CKD due to diabetes and to a lesser extent CKD due to hypertension and other causes outpaced burden expected by demographic expansion. More of the CKD burden (63%) was in low and lower-middle-income countries. There was an inverse relationship between age-standardized CKD DALY rate and health care access and quality of care. Frontier analyses showed significant opportunities for improvement at all levels of the development spectrum. Thus, the global toll of CKD is significant, rising, and unevenly distributed; it is primarily driven by demographic expansion and in some regions a significant tide of diabetes. Opportunities exist to reduce CKD burden at all levels of development.

Monocyte count modifies the association between chronic kidney disease and risk of death
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BACKGROUND: Chronic kidney disease (CKD) is associated with increased all-cause mortality. How non-traditional risk factors modify the mortality risk associated with CKD has not been studied. We approached this question using elevated monocyte count, which is associated with increased risk of death in the general population; however, there is very limited data in CKD. MATERIALS AND METHODS: A national cohort of 1,706,589 U.S. veterans without end-stage renal disease (ESRD) was followed over a median of 9.16 years. Estimated glomerular filtration rate (eGFR; mL/min/1.73m2) was divided into 6 categories: 15 - 30, 30 - 45, 45 - 60, 60 - 90, 90 - 105 (reference), and > 105. Monocyte count (k/cmm) was grouped into quartiles: 0.00 - 0.40 (reference), 0.40 - 0.56, 0.56 - 0.70, and > 0.70. Multinomial logistic regression, Cox proportional hazard regression, and formal interaction analyses on both the multiplicative and additive scales were undertaken. RESULTS: Monocyte count > 0.56 k/cmm was associated with increased risk of death overall (hazard ratio (HR) 1.40, confidence interval (CI) 1.38, 1.41 in monocyte quartile 4) and across each eGFR category. Very high (> 105 mL/min/1.73m2) and low (15 - 30 mL/min/1.73m2) eGFR categories were associated with increased mortality risk (HR 1.40, CI 1.38, 1.42 and HR 2.07, CI 2.03, 2.11, respectively). The mortality risk associated with high monocyte count and low eGFR exhibited a strong negative interaction (p < 0.001). No interaction was noted at very high eGFR. CONCLUSION: While low and very high eGFR were both associated with increased mortality risk, a monocyte count > 0.56 k/cmm only modified the risk associated with low eGFR. This suggests a shared underlying mechanism of death between CKD and high monocyte count.
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Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury.

Proton pump inhibitor (PPI) use is associated with an increased risk of acute kidney injury (AKI), incident chronic kidney disease (CKD), and progression to end-stage renal disease (ESRD). PPI-associated CKD is presumed to be mediated by intervening AKI. However, whether PPI use is associated with an increased risk of chronic renal outcomes in the absence of intervening AKI is unknown. To evaluate this we used the Department of Veterans Affairs national databases to build a cohort of 144,032 incident users of acid suppression therapy that included 125,596 PPI and 18,436 Histamine H2 receptor antagonist (H2 blockers) consumers. Over 5 years of follow-up in survival models, cohort participants were censored at the time of AKI occurrence. Compared with incident users of H2 blockers, incident users of PPIs had an increased risk of an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m2 (hazard ratio 1.19; 95% confidence interval 1.15-1.24), incident CKD (1.26; 1.20-1.33), eGFR decline over 30% (1.22; 1.16-1.28), and ESRD or eGFR decline over 50% (1.30; 1.15-1.48). Results were consistent in models that excluded participants with AKI either before chronic renal outcomes, during the time in the cohort, or before cohort entry. The proportion of PPI effect mediated by AKI was 44.7%, 45.47%, 46.00%, and 46.72% for incident eGFR under 60 ml/min/1.73m2, incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively. Thus, PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI. Hence, reliance on antecedent AKI as warning sign to guard against the risk of CKD among PPI users is not sufficient as a sole mitigation strategy.

Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.

The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

Low levels of high-density lipoprotein cholesterol increase the risk of incident kidney disease and its progression.

Available experimental evidence suggests a role for high-density lipoprotein cholesterol (HDL-C) in incident chronic kidney disease (CKD) and its progression. However, clinical studies are inconsistent. We therefore built a cohort of 1,943,682 male US veterans and used survival models to examine the association between HDL-C and risks of incident CKD or CKD progression (doubling of serum creatinine, eGFR decline of 30% or more), or a composite outcome of ESRD, dialysis, or renal transplantation. Models were adjusted for demographics, comorbid conditions, eGFR, body mass index, lipid parameters, and statin use over a median follow-up of 9 years. Compared to those with HDL-C of 40 mg/dl or more, low HDL-C (under 30 mg/dl) was associated with increased risk of incident eGFR under 60 ml/min/1.73 m(2) (hazard ratio: 1.18; confidence interval: 1.17-1.19) and risk of incident CKD (1.20; 1.18-1.22). Adjusted models demonstrate an association between low HDL-C and doubling of serum creatinine (1.14; 1.12-1.15), eGFR decline of 30% or more (1.13; 1.12-1.14), and the composite renal end point (1.08; 1.06-1.11). Cubic spline analyses of the relationship between HDL-C levels and renal outcomes showed a U-shaped relationship, where risk was increased in lowest and highest deciles of HDL-C. Thus, a significant association exists between low HDL-C levels and risks of incident CKD and CKD progression. Further studies are needed to explain the increased risk of adverse renal outcomes in patients with high HDL-C.

Estimated GFR Trajectories of People Entering CKD Stage 4 and Subsequent Kidney Disease Outcomes and Mortality.

BACKGROUND: Estimated glomerular filtration rate (eGFR) trajectories of people entering chronic kidney disease (CKD) stage 4 and their associations with subsequent kidney disease outcomes or death are not known. STUDY DESIGN: Longitudinal observational cohort study. SETTING & PARTICIPANTS: 26,246 patients in the Veterans Affairs Healthcare System who entered CKD stage 4 in fiscal year 2008 followed up until October 2013. FACTORS: 5-year eGFR trajectories, demographic and health characteristics. OUTCOMES: Composite kidney disease outcome of kidney failure, dialysis therapy or transplantation, and death. RESULTS: Latent class group modeling and functional characterization suggest the presence of 3 distinct trajectory classes: class 1 (72%), consistent slow decline with absolute eGFR change of -2.45 (IQR, -3.89 to -1.16) mL/min/1.73m(2) per year; class 2 (18%), consistent fast decline and eGFR change of -8.60 (IQR, -11.29 to -6.66) mL/min/1.73m(2) per year; and class 3 (10%), early nondecline and late fast decline with eGFR change of -0.4mL/min/1.73m(2) per year in years 1 to 3 and -7.98 and -21.36mL/min/1.73m(2) per year in years 4 and 5, respectively. During 4.34 years of follow-up, 9,809 (37%) patients had the composite kidney disease outcome and 14,550 (55%) patients died. Compared to the referent group (trajectory class 1), HRs for 1-year risk for composite kidney disease outcome for trajectory classes 2 and 3 were 1.13 (95% CI, 1.05-1.22) and 0.67 (95% CI, 0.59-0.75), whereas HRs for 1-year risk for death for classes 2 and 3 were 1.17 (95% CI, 1.10-1.28) and 1.29 (95% CI, 1.18-1.42), respectively. The 1-year risk for composite kidney disease outcome was 32% and was 42% more likely than the risk for death in trajectory classes 1 and 2, respectively, whereas the risk for death was 67% more likely than the risk for composite kidney disease outcome in trajectory class 3. LIMITATIONS: Inclusion criteria and mostly male participants limit generalizability of study results. CONCLUSIONS: We characterized 3 different eGFR trajectory classes of people entering CKD stage 4. Our results suggest that the pattern of eGFR trajectory informs the risk for kidney disease outcomes and death.

Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.

OBJECTIVE: To emulate a randomized target trial to estimate the association between the antiviral drug molnupiravir and hospital admission or death in adults with SARS-CoV-2 infection in the community during the omicron predominant era who were at high risk of progression to severe covid-19. DESIGN: Emulation of a randomized target trial using electronic health records. SETTING: US Department of Veterans Affairs. PARTICIPANTS: 85 998 adults with SARS-CoV-2 infection between 5 January and 30 September 2022 and at least one risk factor for progression to severe covid-19: 7818 participants were eligible for and treated with molnupiravir and 78 180 received no treatment. MAIN OUTCOMES MEASURE: The primary outcome was a composite of hospital admission or death at 30 days. The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and balance baseline characteristics between the groups. The cumulative incidence function was used to estimate the relative risk and the absolute risk reduction at 30 days. RESULTS: Molnupiravir was associated with a reduction in hospital admissions or death at 30 days (relative risk 0.72 (95% confidence interval 0.64 to 0.79)) compared with no treatment; the event rates for hospital admission or death at 30 days were 2.7% (95% confidence interval 2.5% to 3.0%) for molnupiravir and 3.8% (3.7% to 3.9%) for no treatment; the absolute risk reduction was 1.1% (95% confidence interval 0.8% to 1.4%). Molnupiravir appeared to be effective in those who had not been vaccinated against covid-19 (relative risk 0.83 (0.70 to 0.97) and absolute risk reduction 0.9% (0.2% to 1.9%)), had received one or two vaccine doses (0.69 (0.56 to 0.83) and 1.3% (0.7% to 1.9%)), and had received a booster dose (0.71 (0.58 to 0.83) and 1.0% (0.5% to 1.4%)); in those infected during the era when the omicron subvariant BA.1 or BA.2 was predominant (0.72 (0.62 to 0.83) and 1.2% (0.7% to 1.6%)) and when BA.5 was predominant (0.75 (0.66 to 0.86) and 0.9% (0.5% to 1.3%)); and in those with no history of SARS-CoV-2 infection (0.72 (0.64 to 0.81) and 1.1% (0.8% to 1.4%)) and with a history of SARS-CoV-2 infection (0.75 (0.58 to 0.97) and 1.1% (0.1% to 1.8%)). CONCLUSIONS: The findings of this emulation of a randomized target trial suggest that molnupiravir might have reduced hospital admission or death at 30 days in adults with SARS-CoV-2 infection in the community during the recent omicron predominant era who were at high risk of progression to severe covid-19 and eligible for treatment with molnupiravir.

Nirmatrelvir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.

OBJECTIVE: To estimate the effectiveness of nirmatrelvir, compared with no treatment, in reducing admission to hospital or death at 30 days in people infected with the SARS-CoV-2 virus and at risk of developing severe disease, according to vaccination status and history of previous SARS-CoV-2 infection. DESIGN: Emulation of a randomized target trial with electronic health records. SETTING: Healthcare databases of the US Department of Veterans Affairs PARTICIPANTS: 256 288 participants with a SARS-CoV-2 positive test result and at least one risk factor for developing severe covid-19 disease, between 3 January and 30 November 2022. 31 524 were treated with nirmatrelvir within five days of testing positive for SARS-CoV-2 and 224 764 received no treatment. MAIN OUTCOME MEASURES: The effectiveness of starting nirmatrelvir within five days of a positive SARS-CoV-2 test result versus no treatment in reducing the risk of admission to hospital or death at 30 days was estimated in those who were not vaccinated, in those who received one or two doses of vaccine, and those who received a vaccine booster and, separately, in participants with a primary SARS-CoV-2 infection or reinfection. The inverse probability weighting method was used to balance personal and health characteristics between the groups. Relative risk and absolute risk reduction were computed from cumulative incidence at 30 days, estimated by weighted Kaplan-Meier estimator. RESULTS: Among people who were not vaccinated (n=76 763; 5338 nirmatrelvir and 71 425 no treatment), compared with no treatment, the relative risk of nirmatrelvir in reducing admission to hospital or death at 30 days was 0.60 (95% confidence interval 0.50 to 0.71); the absolute risk reduction was 1.83% (95% confidence interval 1.29% to 2.49%). The relative risk and absolute risk reduction, compared with no treatment, were 0.65 (0.57 to 0.74) and 1.27% (0.90% to 1.61%), respectively, in people who received one or two doses of vaccine (n=84 620; 7989 nirmatrelvir and 76 631 no treatment); 0.64 (0.58 to 0.71) and 1.05% (0.85% to 1.27%) in individuals who received a booster dose of vaccine (n=94 905; 18 197 nirmatrelvir and 76 708 no treatment); 0.61 (0.57 to 0.65) and 1.36% (1.19% to 1.53%) in participants with a primary SARS-CoV-2 infection (n=228 081; 26 350 nirmatrelvir and 201 731 no treatment); and 0.74 (0.63 to 0.87) and 0.79% (0.36% to 1.18%) in participants who were reinfected with the SARS-CoV-2 virus (n=28 207; 5174 nirmatrelvir and 23 033 no treatment). Nirmatrelvir was associated with a reduced risk of admission to hospital or death in those aged ≤65 years and > 65 years; in men and women; in black and white participants; in those with 1-2, 3-4, and ≥5 risk factors for progression to severe covid-19 illness; and in those infected during the omicron BA.1 or BA.2 predominant era, and the BA.5 predominant era. CONCLUSIONS: In people with SARS-CoV-2 infection who were at risk of developing severe disease, compared with no treatment, nirmatrelvir was associated with a reduced risk of admission to hospital or death at 30 days in people who were not vaccinated, vaccinated, and had received a booster vaccine, and in those with a primary SARS-CoV-2 infection and reinfection.

Postacute sequelae of COVID-19 at 2 years.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6-89.6) and 642.8 (95% CI: 596.9-689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9-31.0%) and 21.3% (18.2-24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.

BACKGROUND: Randomised clinical trials showed that compared with placebo, SGLT2 inhibitors and GLP-1 receptor agonists reduced risk of adverse cardiovascular events. The evidence base for the older antihyperglycaemic drug classes (DPP-4 inhibitors and sulfonylureas) is generally less well developed. Because most randomised trials evaluated one antihyperglycaemic medication versus placebo, a head-to-head comparative effectiveness analysis of the newer drug classes (SGLT2 inhibitors vs GLP-1 receptor agonists) or newer (SGLT2 inhibitors or GLP-1 receptor agonists) versus older (DPP-4 inhibitors or sulfonylureas) drug classes on risk of major adverse cardiovascular events (MACE) is not available. In this study, we aimed to evaluate the comparative effectiveness of incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas on risk of MACE. METHODS: We first specified the protocol of a four-arm randomised pragmatic clinical trial and then emulated it using the health-care databases of the US Department of Veterans Affairs. We built a cohort of metformin users with incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas between Oct 1, 2016 and Sept 30, 2021, and followed up until Dec 31, 2022. We used the overlap weighting approach to balance the treatment groups using a battery of predefined variables and a set of algorithmically selected variables from high-dimensional data domains. Both intention-to-treat and per-protocol analyses (the latter estimated the effect of maintained use of the antihyperglycaemic throughout follow-up) were conducted to estimate risk of MACE-defined as a composite endpoint of stroke, myocardial infarction, and all-cause mortality. FINDINGS: The final cohort consisted of 283 998 new users of SGLT2 inhibitors (n=46 516), GLP-1 receptor agonists (n=26 038), DPP-4 inhibitors (n=55 310), or sulfonylureas (n=156 134). In intention-to-treat analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with lower risk of MACE (hazard ratio [HR] 0·77 [95% CI 0·74-0.80], 0·78 [0·74-0·81), and 0·90 [0·86-0.93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·86 [0·82-0·89] and 0·86 [0·82-0·90], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 0·99 (0·94-1·04). In per-protocol analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP1 receptor agonists, and DPP-4 inhibitors were associated with reduced risk of MACE (HR 0·77 [95% CI 0·73-0·82], 0·77 [0·72-0·82], and 0·88 [0·83-0·93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·88 [0·83-0·93] and 0·88 [0·82-0·93], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 1·01 (0·94-1·07). INTERPRETATION: Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with reduced risk of MACE compared with DPP-4 inhibitors or sulfonylureas. DPP-4 inhibitors were associated with reduced risk of MACE compared with sulfonylureas. There was no statistically significant difference in risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists. The results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy. FUNDING: US Department of Veterans Affairs and the American Society of Nephrology.

Long COVID after breakthrough SARS-CoV-2 infection.

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-also referred to as Long COVID-have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

Long-term cardiovascular outcomes of COVID-19.

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

Acute and postacute sequelae associated with SARS-CoV-2 reinfection.

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93-2.45), hospitalization (HR = 3.32, 95% CI 3.13-3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.