Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

BackgroundInformation about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19. MethodsWe conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. ResultsParticipants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] - 13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI - 16.07 to -7.35). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged [≥]65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups. ConclusionsNirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral.

Design and Analysis of Outcomes following SARS-CoV-2 Infection in Veterans

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSUnderstanding how SARS-CoV-2 infection impacts long-term patient outcomes requires identification of comparable persons with and without infection. We report the design and implementation of a matching strategy employed by the Department of Veterans Affairs (VA) COVID-19 Observational Research Collaboratory (CORC) to develop comparable cohorts of SARS-CoV-2 infected and uninfected persons for the purpose of inferring potential causative long-term adverse effects of SARS-CoV-2 infection in the Veteran population. MethodsIn a retrospective cohort study, we identified VA health care system patients who were and were not infected with SARS-CoV-2 on a rolling monthly basis. We generated matched cohorts utilizing a combination of exact and time-varying propensity score matching based on electronic health record (EHR)-derived covariates that can be confounders or risk factors across a range of outcomes. ResultsFrom an initial pool of 126,689,864 person-months of observation, we generated final matched cohorts of 208,536 Veterans infected between March 2020-April 2021 and 3,014,091 uninfected Veterans. Matched cohorts were well-balanced on all 38 covariates used in matching after excluding patients for: no VA health care utilization; implausible age, weight, or height; living outside of the 50 states or Washington, D.C.; prior SARS-CoV-2 diagnosis per Medicare claims; or lack of a suitable match. Most Veterans in the matched cohort were male (88.3%), non-Hispanic (87.1%), white (67.2%), and living in urban areas (71.5%), with a mean age of 60.6, BMI of 31.3, Gagne comorbidity score of 1.4 and a mean of 2.3 CDC high-risk conditions. The most common diagnoses were hypertension (61.4%), diabetes (34.3%), major depression (32.2%), coronary heart disease (28.5%), PTSD (25.5%), anxiety (22.5%), and chronic kidney disease (22.5%). ConclusionsThis successful creation of matched SARS-CoV-2 infected and uninfected patient cohorts from the largest integrated health system in the United States will support cohort studies of outcomes derived from EHRs and sample selection for qualitative interviews and patient surveys. These studies will increase our understanding of the long-term outcomes of Veterans who were infected with SARS-CoV-2.

Receipt of anti-SARS-CoV-2 pharmacotherapies among U.S. Veterans with mild to moderate COVID-19, January-February 2022

BackgroundOlder adults and persons with medical co-morbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19-related hospitalization and death have been authorized for use. We describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Health Administration. MethodsWe conducted a retrospective cohort study among Veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. We compared receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir plus ritonavir, molnupiravir, or remdesivir versus no antiviral or monoclonal antibody treatment according to demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination using multivariable logistic regression. ResultsDuring January and February 2022, 16,546 courses of sotrovimab, nirmatrelvir, and molnupiravir were allocated across the Veterans Health Administration. Among 111,717 Veterans testing positive for SARS-CoV-2, 4,233 (3.8%) received any COVID-19 pharmacotherapy, including 2,870 of 92,396 (3.1%) in January and 1,363 of 19,321 (7.1%) in February. Among a subset of 56,206 Veterans with documented COVID-19-related symptoms in the 30 days preceding positive SARS-CoV-2 test, 3,079 of 53,206 (5.5%) received any COVID-19 pharmacotherapy. Untreated Veterans had a median age of 60 years (interquartile range [IQR] 46-71 years) and median 3 underlying medical conditions (IQR 2-5). Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] 1.66, 95% confidence interval [CI] 1.52-1.80, 65-74 versus 50-64 years; aOR 1.67, 95% CI 1.53-1.84 [≥]75 versus 50-64 years) and have a higher number of underlying conditions (aOR 1.63, 95% CI 1.48-1.79, 3-4 versus 1-2 conditions; aOR 2.17, 95% CI 1.98-2.39, [≥]5 versus 1-2 conditions). Persons of Black versus White race (aOR 0.65, 95% CI 0.60-0.72) and well as persons of Hispanic ethnicity (aOR 0.88, 95% CI 0.77-0.99) were less likely to receive treatment. Conclusions and RelevanceAlthough supply of outpatient COVID-19 pharmacotherapies during January and February 2022 was limited, prescription of these pharmacotherapies was underutilized, consistent with early national patterns in dispensing. Racial and ethnic minorities were less likely to receive any pharmacotherapy.

Effectiveness of mRNA COVID-19 vaccine boosters against infection, hospitalization and death: a target trial emulation in the omicron (B.1.1.529) variant era

AbstractO_ST_ABSBackgroundC_ST_ABSThe effectiveness of a 3rd mRNA COVID-19 vaccine ("booster") dose against the omicron (B.1.1.529) variant is uncertain especially in older, high-risk populations. ObjectiveTo determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization and death in the omicron era by type of booster, type of primary vaccine, time since primary vaccine, age and comorbidity burden. DesignTarget trial emulation study comparing booster vaccination versus no booster. SettingU.S. Department of Veterans Affairs (VA) healthcare system Participants and InterventionAmong persons who had received two mRNA COVID-19 vaccine doses at least 5 months earlier, we designed this retrospective matched cohort study to emulate a target trial of booster mRNA vaccination (BNT162b2 or mRNA-1273) versus no booster, conducted from 12/01/2021 to 03/31/2022. MeasurementsBooster VE. ResultsEach group included 490,838 well-matched persons, predominantly male (88%), mean age 63.0{+/-}14.0 years, followed for up to 121 days (mean 79.8 days). Booster VE >10 days after booster was 42.3% (95% CI 40.6-43.9) against SARS-CoV-2 infection, 53.3% (48.1-58.0) against SARS-CoV-2-related hospitalization and 79.1% (71.2-84.9) against SARS-CoV-2-related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups or primary vaccination regimens, but was significantly higher with longer time since primary vaccination and with higher comorbidity burden. LimitationsPredominantly male population. ConclusionsBooster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden. Primary Funding Source: Department of Veterans Affairs

Lower High-Density Lipoprotein Cholesterol Concentration Is Independently Associated with Greater Future Accumulation of Intra-Abdominal Fat

Background@#Both intra-abdominal fat (IAF) and high-density lipoprotein cholesterol (HDL-C) are known to be associated with cardiometabolic health. We evaluated whether the accumulation of computed tomography (CT)-measured IAF over 5 years was related to baseline HDL-C concentration in a prospective cohort study. @*Methods@#All participants were Japanese-Americans between the ages of 34 and 74 years. Plasma HDL-C concentration and CT measurements of IAF, abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas were assessed at baseline and at 5-year follow-up visits. @*Results@#A total of 397 subjects without diabetes were included. The mean±standard deviation HDL-C concentration was 51.6±13.0 mg/dL in men and 66.0±17.0 mg/dL in women, and the IAF was 91.9±48.4 cm2 in men and 63.1±39.5 cm2 in women. The baseline plasma concentration of HDL-C was inversely associated with the change in IAF over 5 years using multivariable regression analysis with adjustment for age, sex, family history of diabetes, weight change over 5 years, and baseline measurements of body mass index, IAF, abdominal SCF, abdominal circumference, thigh SCF, and homeostatic model assessment for insulin resistance. @*Conclusion@#These results demonstrate that HDL-C concentration significantly predicts future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in Japanese-American men and women without diabetes.

Lower High-Density Lipoprotein Cholesterol Concentration Is Independently Associated with Greater Future Accumulation of Intra-Abdominal Fat

Background@#Both intra-abdominal fat (IAF) and high-density lipoprotein cholesterol (HDL-C) are known to be associated with cardiometabolic health. We evaluated whether the accumulation of computed tomography (CT)-measured IAF over 5 years was related to baseline HDL-C concentration in a prospective cohort study. @*Methods@#All participants were Japanese-Americans between the ages of 34 and 74 years. Plasma HDL-C concentration and CT measurements of IAF, abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas were assessed at baseline and at 5-year follow-up visits. @*Results@#A total of 397 subjects without diabetes were included. The mean±standard deviation HDL-C concentration was 51.6±13.0 mg/dL in men and 66.0±17.0 mg/dL in women, and the IAF was 91.9±48.4 cm2 in men and 63.1±39.5 cm2 in women. The baseline plasma concentration of HDL-C was inversely associated with the change in IAF over 5 years using multivariable regression analysis with adjustment for age, sex, family history of diabetes, weight change over 5 years, and baseline measurements of body mass index, IAF, abdominal SCF, abdominal circumference, thigh SCF, and homeostatic model assessment for insulin resistance. @*Conclusion@#These results demonstrate that HDL-C concentration significantly predicts future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in Japanese-American men and women without diabetes.

Clinical Outcomes of COVID-19 Patients with Type 2 Diabetes: A Population-Based Study in Korea

Background@#The aim of this study was to evaluate clinical outcomes in coronavirus disease 2019 (COVID-19) positive patients with type 2 diabetes compared to those without diabetes in Korea. @*Methods@#We extracted claims data for patients diagnosed with COVID-19 from the National Health Insurance Service database in Korea from January 20, 2020 to March 31, 2020. We followed up this cohort until death from COVID-19 or discharge from hospital. @*Results@#A total of 5,473 patients diagnosed with COVID-19 were analyzed, including 495 with type 2 diabetes and 4,978 without diabetes. Patients with type 2 diabetes were more likely to be treated in the intensive care unit (ICU) (P<0.0001). The incidence of inhospital mortality was higher in patients with type 2 diabetes (P<0.0001). After adjustment for age, sex, insurance status, and comorbidities, odds of ICU admission (adjusted odds ratio [OR], 1.59; 95% confidence interval [CI], 1.02 to 2.49; P=0.0416) and in-hospital mortality (adjusted OR, 1.90; 95% CI, 1.13 to 3.21; P=0.0161) among patients with COVID-19 infection were significantly higher in those with type 2 diabetes. However, there was no significant difference between patients with and without type 2 diabetes in ventilator, oxygen therapy, antibiotics, antiviral drugs, antipyretics, and the incidence of pneumonia after adjustment. @*Conclusion@#COVID-19 positive patients with type 2 diabetes had poorer clinical outcomes with higher risk of ICU admission and in-hospital mortality than those without diabetes. Therefore, medical providers need to consider this more serious clinical course when planning and delivering care to type 2 diabetes patients with COVID-19 infection.

Apolipoprotein B Levels Predict Future Development of Hypertension Independent of Visceral Adiposity and Insulin Sensitivity

Background@#High plasma apolipoprotein B (apoB) levels have been shown to be associated with hypertension, central obesity, and insulin resistance in cross-sectional research. However, it is unclear whether apoB levels predict future hypertension independent of body composition and insulin sensitivity. Therefore, we prospectively investigated whether plasma apoB concentrations independently predicted the risk of hypertension in a cohort of Japanese Americans. @*Methods@#A total of 233 normotensive Japanese Americans (77 men, 156 women; mean age, 46.4±11.0 years) were followed over 10 years to monitor them for the development of hypertension. Fasting plasma concentrations of apoB, glucose, and insulin were measured at baseline. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). The abdominal visceral and subcutaneous fat areas were measured at baseline using computed tomography. Logistic regression analysis was used to estimate the association between apoB concentrations and the odds of incident hypertension. @*Results@#The 10-year cumulative incidence of hypertension was 21.5%. The baseline apoB level was found to be positively associated with the odds of incident hypertension over 10 years after adjustment for age, sex, body mass index, systolic blood pressure, abdominal visceral fat area, abdominal subcutaneous fat area, total plasma cholesterol concentration, diabetes status, and HOMA-IR at baseline (odds ratio and 95% confidence interval for a 1-standard deviation increase, 1.89 [1.06 to 3.37]; P=0.030). @*Conclusion@#Higher apoB concentrations predicted greater risks of future hypertension independent of abdominal visceral fat area and insulin sensitivity in Japanese Americans.

Intra-Abdominal Fat and High Density Lipoprotein Cholesterol Are Associated in a Non-Linear Pattern in Japanese-Americans

Background@#We describe the association between high density lipoprotein cholesterol (HDL-C) concentration and computed tomography (CT)-measured fat depots. @*Methods@#We examined the cross-sectional associations between HDL-C concentration and intra-abdominal (IAF), abdominal subcutaneous (SCF), and thigh fat (TF) areas in 641 Japanese-American men and women. IAF, SCF, and TF were measured by CT at the level of the umbilicus and mid-thigh. The associations between fat area measurements and HDL-C were examined using multivariate linear regression analysis adjusting for age, sex, diabetes family history, homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Non-linearity was assessed using fractional polynomials. @*Results@#Mean±standard deviation of HDL-C concentration and IAF in men and women were 1.30±0.34 mg/dL, 105±55.3 cm2, and 1.67±0.43 mg/dL, 74.4±46.6 cm2 and differed significantly by gender for both comparisons (P<0.001). In univariate analysis, HDL-C concentration was significantly associated with CT-measured fat depots. In multivariate analysis, IAF was significantly and non-linearly associated with HDL-C concentration adjusted for age, sex, BMI, HOMA-IR, SCF, and TF (IAF: β=–0.1012, P <0.001; IAF2: β=0.0008, P<0.001). SCF was also negatively and linearly associated with HDL-C (β=–0.4919, P=0.001). @*Conclusion@#HDL-C does not linearly decline with increasing IAF in Japanese-Americans. A more complex pattern better fits this association.

Clinical Outcomes of COVID-19 Patients with Type 2 Diabetes: A Population-Based Study in Korea

Background@#The aim of this study was to evaluate clinical outcomes in coronavirus disease 2019 (COVID-19) positive patients with type 2 diabetes compared to those without diabetes in Korea. @*Methods@#We extracted claims data for patients diagnosed with COVID-19 from the National Health Insurance Service database in Korea from January 20, 2020 to March 31, 2020. We followed up this cohort until death from COVID-19 or discharge from hospital. @*Results@#A total of 5,473 patients diagnosed with COVID-19 were analyzed, including 495 with type 2 diabetes and 4,978 without diabetes. Patients with type 2 diabetes were more likely to be treated in the intensive care unit (ICU) (P<0.0001). The incidence of inhospital mortality was higher in patients with type 2 diabetes (P<0.0001). After adjustment for age, sex, insurance status, and comorbidities, odds of ICU admission (adjusted odds ratio [OR], 1.59; 95% confidence interval [CI], 1.02 to 2.49; P=0.0416) and in-hospital mortality (adjusted OR, 1.90; 95% CI, 1.13 to 3.21; P=0.0161) among patients with COVID-19 infection were significantly higher in those with type 2 diabetes. However, there was no significant difference between patients with and without type 2 diabetes in ventilator, oxygen therapy, antibiotics, antiviral drugs, antipyretics, and the incidence of pneumonia after adjustment. @*Conclusion@#COVID-19 positive patients with type 2 diabetes had poorer clinical outcomes with higher risk of ICU admission and in-hospital mortality than those without diabetes. Therefore, medical providers need to consider this more serious clinical course when planning and delivering care to type 2 diabetes patients with COVID-19 infection.

Higher High Density Lipoprotein 2 (HDL2) to Total HDL Cholesterol Ratio Is Associated with a Lower Risk for Incident Hypertension

BACKGROUND: Recent studies have suggested that high density lipoprotein (HDL) cholesterol is inversely associated with the development of hypertension. We aimed to determine the association between different HDL cholesterol subclasses and risk of future hypertension. METHODS: A total of 270 Japanese Americans (130 men, 140 women) without hypertension between the ages of 34 to 75 years were enrolled. Blood pressure was measured with a mercury sphygmomanometer, and average blood pressure was calculated. Incident hypertension was determined 5 to 6 and 10 to 11 years after enrollment. HDL2, HDL3, and total HDL cholesterol were measured at baseline. RESULTS: During 10 years of follow-up, the cumulative incidence of hypertension was 28.1% (76/270). In univariate analysis, age, diabetes, waist circumference, systolic and diastolic blood pressure, fasting glucose, insulin resistance index, total and low density lipoprotein cholesterol, and visceral adipose tissue were significant predictors for incident hypertension. Among the HDL cholesterol subclass, HDL2 cholesterol was inversely associated with hypertension incidence, but both total and HDL3 cholesterol were not. In addition, HDL2/HDL cholesterol was inversely associated with future hypertension risk. In multivariate analysis, age (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26 to 2.31; P=0.001), systolic blood pressure (OR, 1.83; 95% CI, 1.31 to 2.56; P < 0.001), and HDL2/HDL cholesterol (OR, 0.71; 95% CI, 0.52 to 0.98; P=0.035), were associated with future development of hypertension. CONCLUSION: A higher proportion of HDL2 cholesterol among total HDL cholesterol predicted a lower risk for incident hypertension. However, concentrations of total HDL, HDL2, and HDL3 cholesterol were not independent predictors of incident hypertension.

Response: Association of Thigh Muscle Mass with Insulin Resistance and Incident Type 2 Diabetes Mellitus in Japanese Americans (Diabetes Metab J 2018;42:488–95)

No abstract available.

Association of Thigh Muscle Mass with Insulin Resistance and Incident Type 2 Diabetes Mellitus in Japanese Americans

BACKGROUND: Skeletal muscle plays a major role in glucose metabolism. We investigated the association between thigh muscle mass, insulin resistance, and incident type 2 diabetes mellitus (T2DM) risk. In addition, we examined the role of body mass index (BMI) as a potential effect modifier in this association. METHODS: This prospective study included 399 Japanese Americans without diabetes (mean age 51.6 years) who at baseline had an estimation of thigh muscle mass by computed tomography and at baseline and after 10 years of follow-up a 75-g oral glucose tolerance test and determination of homeostasis model assessment of insulin resistance (HOMA-IR). We fit regression models to examine the association between thigh muscle area and incidence of T2DM and change in HOMA-IR, both measured over 10 years. RESULTS: Thigh muscle area was inversely associated with future HOMA-IR after adjustment for age, sex, BMI, HOMA-IR, fasting plasma glucose, total abdominal fat area, and thigh subcutaneous fat area at baseline (P=0.033). The 10-year cumulative incidence of T2DM was 22.1%. A statistically significant interaction between thigh muscle area and BMI was observed, i.e., greater thigh muscle area was associated with lower risk of incident T2DM for subjects at lower levels of BMI, but this association diminished at higher BMI levels. CONCLUSION: Thigh muscle mass area was inversely associated with future insulin resistance. Greater thigh muscle area predicts a lower risk of incident T2DM for leaner Japanese Americans.

The Evidence for an Obesity Paradox in Type 2 Diabetes Mellitus

Although overweight/obesity is a major risk factor for the development of type 2 diabetes mellitus, there is increasing evidence that overweight or obese patients with type 2 diabetes mellitus experience lower mortality compared with patients of normal weight. This paradoxical finding, known as the “obesity paradox,” occurs in other chronic diseases, and in type 2 diabetes mellitus is particularly perplexing given that lifestyle intervention with one goal being weight reduction is an important feature of the management of this condition. We summarize in this review the findings from clinical and epidemiologic studies that have investigated the association between overweight and obesity (usually assessed using body mass index [BMI]) and mortality in type 2 diabetes mellitus and discuss potential causes of the obesity paradox. We conclude that most studies show evidence of an obesity paradox, but important conflicting findings still exist. We also evaluate if potential bias might explain the obesity paradox in diabetes, including, for example, the presence of confounding factors, measurement error due to use of BMI as an index of obesity, and reverse causation.

Predictors of Incident Type 2 Diabetes Mellitus in Japanese Americans with Normal Fasting Glucose Level

BACKGROUND: Little is known about the natural course of normal fasting glucose (NFG) in Asians and the risk factors for future diabetes. METHODS: A total of 370 Japanese Americans (163 men, 207 women) with NFG levels and no history of diabetes, aged 34 to 75 years, were enrolled. Oral glucose tolerance tests were performed at baseline, 2.5, 5, and 10 years after enrollment. RESULTS: During 10 years of follow-up, 16.1% of participants met criteria for diabetes diagnosis, and 39.6% of subjects still had NFG levels at the time of diabetes diagnosis. During 5 years of follow-up, age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01 to 1.10; P=0.026) and family history of diabetes (OR, 3.24; 95% CI, 1.42 to 7.40; P=0.005) were independently associated with future diabetes diagnosis; however, fasting glucose level was not an independent predictor. During 10 years of follow-up, family history of diabetes (OR, 2.76; 95% CI, 1.37 to 5.54; P=0.004), fasting insulin level (OR, 1.01; 95% CI, 1.00 to 1.02; P=0.037), and fasting glucose level (OR, 3.69; 95% CI, 1.13 to 12.01; P=0.030) were associated with diabetes diagnosis independent of conventional risk factors for diabetes. CONCLUSION: A substantial number of subjects with NFG at baseline still remained in the NFG range at the time of diabetes diagnosis. A family history of diabetes and fasting insulin and glucose levels were associated with diabetes diagnosis during 10 years of follow-up; however, fasting glucose level was not associated with diabetes risk within the relatively short-term follow-up period of 5 years in subjects with NFG.