Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: A Scandinavian cohort study.

BACKGROUND AND AIMS: Clinical trials suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may have beneficial effects on NAFLD, but the impact on hard hepatic end points is unknown. We assessed the association between the use of GLP-1 receptor agonists and the risk of serious liver events in routine clinical practice. APPROACH AND RESULTS: Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, 2007-2020, including 91,479 initiators of GLP-1 receptor agonists and 244,004 initiators of the active comparator, dipeptidyl peptidase-4 inhibitors, without a history of chronic liver disease other than NAFLD/NASH. The primary outcome was serious liver events: a composite of incident compensated and decompensated cirrhosis and HCC. Secondary outcomes were the individual components of the primary outcome. Cox regression was used to estimate HRs, using propensity score weighting to control for confounding. Users of GLP-1 receptor agonists had 608 serious liver events (adjusted incidence rate: 16.9 events per 10,000 person-years), compared with 1770 events among users of dipeptidyl peptidase-4 inhibitors (19.2 events per 10,000 person-years). The adjusted HR was 0.85 (95% CI: 0.75 to 0.97), and the rate difference was -2.1 (-4.4 to 0.1) events per 10,000 person-years. In secondary outcome analyses, the adjusted HR was 0.85 (0.75 to 0.97) for compensated and decompensated cirrhosis and 1.05 (0.80 to 1.39) for HCC. CONCLUSIONS: The use of GLP-1 receptor agonists was associated with a significantly reduced risk of serious liver events, driven by a reduction of compensated and decompensated cirrhosis.

Depression and anxiety-related disorders and suicide among Swedish male elite football players: a nationwide cohort study.

OBJECTIVE: To assess whether male elite football players, during and after their active career, were at increased risk of depression and anxiety-related disorders and suicide, as compared with the general male population. METHODS: We included male football players active in the Swedish top division 1924-2019 and general male population (matched to football players based on age and region of residence) aged <65 years in 1997. Using nationwide registers, we followed the football players from their first season in the top division (or the date of their first registered residency in Sweden) or 1 January 1997, and compared the risk of depression and anxiety-related disorders (captured through diagnoses from hospital admissions and outpatient visits, and use of prescription drugs) among football players versus controls. In a secondary analysis using data from death certificates, we compared the risk of suicide between football players and general population males who were alive in 1969 (when cause of death became available) . RESULTS: During follow-up through 31 December 2020, 504 (13.6%) of 3719 football players and 7455 (22.3%) of 33 425 general population males had a depression or anxiety-related disorder. In analyses accounting for age, region of residence and calendar time, the risk of anxiety and depression-related disorders was lower among football players versus general population males (HR 0.61, 95% CI 0.55 to 0.66). The protective association was attenuated with increasing age, and from around age 70 years the risk was similar in the two groups. The risk of suicide was lower among football players versus general population males (HR 0.48, 95% CI 0.32 to 0.72). CONCLUSIONS: In this nationwide cohort study in Sweden, elite male football players had a lower risk of depression and anxiety-related disorders and suicide as compared with the general population.

Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study.

BACKGROUND & AIMS: Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction. METHODS: Using data from nationwide registers in Sweden, Denmark, and Norway, 2013-2021, we conducted 2 cohort studies, one for DPP4 inhibitors and one for GLP-1 receptor agonists, to investigate the risk of intestinal obstruction as compared with an active comparator drug class (sodium-glucose co-transporter 2 [SGLT2] inhibitors). RESULTS: Among 19,0321 new users of DPP4 inhibitors (median (interquartile range [IQR]) follow-up time, 1.3 [0.6-2.6] years) and 139,315 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.7] years), 919 intestinal obstruction events occurred. Use of DPP4 inhibitors, as compared with SGLT2 inhibitors, was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 2.0 vs 1.8 per 1000 person-years; hazard ratio, 1.13; 95% confidence interval, 0.96-1.34). Among 121,254 new users of GLP-1 receptor agonists (median [standard deviation] follow-up time, 0.9 [0.4-1.9] years) and 185,027 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.8] years), 557 intestinal obstruction events occurred. Use of GLP-1 receptor agonists was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 1.3 vs 1.6 per 1000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.69-1.01). CONCLUSIONS: In this analysis of nationwide data from 3 countries, previous safety signals indicating an increased risk of intestinal obstruction with use of DPP4 inhibitors and GLP-1 receptor agonists were not confirmed.

Oral Fluoroquinolone Use and the Risk of Acute Liver Injury: A Nationwide Cohort Study.

BACKGROUND: Antibiotics are considered to be among the most frequent causes of drug-related acute liver injury (ALI). Although many ALIs have mild and reversible clinical outcomes, there is substantial risk of severe reactions leading to acute liver failure, need for liver transplant, and death. Recent studies have raised concerns of hepatotoxic potential related to the use of fluoroquinolones. METHODS: This study examined the risk of ALI associated with oral fluoroquinolone treatment compared with amoxicillin (419 930 courses, propensity score matched 1:1). The information on drug use was collected from a national, registry-based cohort derived from all Swedish adults aged 40-85 years. RESULTS: During a follow-up period of 60 days, users of oral fluoroquinolones had a >2-fold risk of ALI compared to users of amoxicillin (hazard ratio, 2.32 [95% confidence interval {CI}, 1.01-5.35). The adjusted absolute risk difference for use of fluoroquinolones as compared to amoxicillin was 4.94 (95% CI, .04-16.3) per 1 million episodes. CONCLUSIONS: In this propensity score-matched study, fluoroquinolone treatment was associated with an increased risk of ALI in the first 2 months after starting treatment.

Selection of Comparator Group in Observational Drug Safety Studies: Alternatives to the Active Comparator New User Design.

A valid study design is essential when assessing the safety of drugs based on observational data. The comparator group is a key element of the design and can greatly influence the results. The active comparator new user design is a go-to design in observational drug safety research where a target trial of initiation of a study drug versus usual care is emulated. A comparison with another treatment that targets similar patients as the study drug and has no effect on the outcome has great potential to reduce bias. However, the active comparator new user design can be difficult to implement because no suitable comparator drug is available or because it requires extensive exclusion of study drug initiators. In this analysis, we evaluated alternative study designs that can be used in drug safety assessments when the active comparator new user design is not optimal. Using target trial emulation as a common framework, we defined and evaluated the following designs: traditional no use, no-use episodes, active comparator new user, prevalent new user, generalized prevalent new user, and hierarchical prevalent new user. We showed that all designs can be implemented by using sequential cohorts and simply altering the patient selection criteria, i.e., identifying increasingly restrictive cohorts. In this way, all designs are nested in each other and the differences between them can be demonstrated clearly. We concluded that many study-specific factors need to be considered when choosing a design, including indication, available comparator drugs, treatment patterns, potential effect modification, and sample size.

The comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A Scandinavian cohort study.

AIM: To assess the comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in routine clinical practice. MATERIALS AND METHODS: A cohort study of nationwide registers from Sweden, Denmark, and Norway, including 87 525 new users of SGLT2 inhibitors and 63 921 new users of GLP-1 receptor agonists, was conducted using data from 2013-2018. Co-primary outcomes, analysed using an intention-to-treat exposure definition, were major adverse cardiovascular events (MACE; myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure), and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). RESULTS: Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a higher risk of MACE (adjusted incidence rate: 15.2 vs. 14.4 events per 1000 person-years; HR 1.07 [95% CI 1.01-1.15]), a similar risk of heart failure (6.0 vs. 6.0 events per 1000 person-years; HR 1.02 [0.92-1.12]), and a lower risk of serious renal events (2.9 vs. 4.0 events per 1000 person-years; HR 0.76 [0.66-0.87]). In as-treated analyses, the HR (95% CI) was 1.11 (1.00-1.24) for MACE, 0.88 (0.74-1.04) for heart failure, and 0.60 (0.47-0.77) for serious renal events. In secondary outcome analyses, use of SGLT2 inhibitors versus GLP-1 receptor agonists was not associated with statistically significant differences for the risk of myocardial infarction (HR 1.09 [95% CI 1.00-1.19]), cardiovascular death (HR 0.97 [95% CI 0.84-1.12]), death from renal causes (HR 0.75 [95% CI 0.41-1.35]), or any cause death (HR 1.01 [95% CI 0.94-1.09]), while the risk of stroke was higher (HR 1.14 [95% CI 1.03-1.26]), and the risk of renal replacement therapy (HR 0.74 [95% CI 0.56-0.97]) and hospitalization for renal events (HR 0.75 [95% CI 0.65-0.88]) were lower among users of SGLT2 inhibitors. CONCLUSIONS: Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a similar risk of heart failure and a lower risk of serious renal events, while use of GLP-1 receptor agonists versus SGLT2 inhibitors was associated with a slightly lower risk of MACE. In as-treated analyses, the associations with MACE and serious renal events increased in magnitude, and the HR for heart failure tended towards a protective association for SGLT2 inhibitors.

Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study.

AIMS/HYPOTHESIS: Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. METHODS: We used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. RESULTS: The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). CONCLUSIONS/INTERPRETATION: In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.

Proton-Pump Inhibitor Use and the Risk of Community-Associated Clostridium difficile Infection.

BACKGROUND: Proton-pump inhibitors (PPIs) have been reported to increase the risk of community-associated Clostridium difficile infection (CDI), but the association remains disputed. METHODS: A nationwide cohort study among adults in Denmark, 2010-2013, linking register data on C. difficile testing, filled prescriptions, and patient characteristics. All incident episodes of community-associated CDI (ie, positive culture, molecular assay, or toxin test in individuals without previous hospitalization in the prior 12 weeks and without a positive test for C. difficile in the prior 8 weeks) were identified in the Danish National Microbiological Database. Self-controlled case-series analyses were used to estimate incidence rate ratios (IRRs) for community-associated CDI, comparing periods with and without exposure to PPIs. By design, models took fixed confounders such as chronic disease, genetics, and socioeconomic status into account; further, time-varying confounders, including hospital stay and antibiotic and corticosteroid use were adjusted for. RESULTS: 3583 episodes of community-associated CDI were identified, of which 964 occurred during current use of PPIs, 324 occurred 0-6 months after treatment cessation, 123 occurred 6-12 months after treatment cessation, and 2172 occurred during time periods without use of PPIs. The adjusted IRR was 2.03 (95% confidence interval, 1.74-2.36), comparing use of PPI with nonuse. The increased risk remained elevated in later time periods: 1.54 (1.31-1.80) for 0-6 months, 1.24 (1.00-1.53) for 6-12 months after current use. CONCLUSIONS: Use of PPIs was associated with moderately increased risk of community-associated CDI. The risk remained elevated up to 1 year after PPI treatment had ended.

Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes.

BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine is recommended for all girls and women 9 to 26 years of age. Some women will have inadvertent exposure to vaccination during early pregnancy, but few data exist regarding the safety of the quadrivalent HPV vaccine in this context. METHODS: We assessed a cohort that included all the women in Denmark who had a pregnancy ending between October 1, 2006, and November 30, 2013. Using nationwide registers, we linked information on vaccination, adverse pregnancy outcomes, and potential confounders among women in the cohort. Women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. Outcomes included spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, and preterm birth. RESULTS: In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect (65 cases among 1665 exposed pregnancies and 220 cases among 6660 unexposed pregnancies; prevalence odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20 cases among 463 exposed pregnancies and 131 cases among 1852 unexposed pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among 1774 exposed pregnancies and 407 cases among 7096 unexposed pregnancies; prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among 1768 exposed pregnancies and 277 cases among 7072 unexposed pregnancies; prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171 cases among 1768 exposed pregnancies and 783 cases among 7072 unexposed pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases among 501 exposed pregnancies and 4 cases among 2004 unexposed pregnancies; hazard ratio, 2.43; 95% CI, 0.45 to 13.21). CONCLUSIONS: Quadrivalent HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes than no such exposure. (Funded by the Novo Nordisk Foundation and the Danish Medical Research Council.).

Long-Term Risk of Cardiovascular Death With Use of Clarithromycin and Roxithromycin: A Nationwide Cohort Study.

Recent studies have raised concern that macrolide antibiotics may be associated with an increased long-term risk of cardiovascular death. We examined the 1-year risk associated with treatment with clarithromycin (n = 187,887) or roxithromycin (n = 698,899) compared with penicillin V (n = 3,473,081), matched 1:4 on propensity score, in a nationwide, registry-based cohort study in Danish outpatients, 1997-2011. Among clarithromycin courses, the rate ratio for cardiovascular death was 1.24 (95% confidence interval (CI): 0.96, 1.59). Among roxithromycin courses, the rate ratio was 0.99 (95% CI: 0.86, 1.16). In analyses by time after treatment start, the rate ratio associated with clarithromycin was 1.66 (95% CI: 0.98, 2.79) during days 0-7. This was attenuated in later time periods (days 8-89, rate ratio = 1.30, 95% CI: 0.88, 1.94; and days 90-364, rate ratio = 0.96, 95% CI: 0.63, 1.47). For roxithromycin, the rate ratios were 0.88 (95% CI: 0.59, 1.32) during days 0-7, 1.17 (95% CI: 0.92, 1.48) during days 8-89, and 0.88 (95% CI: 0.70, 1.10) during days 90-364. We found no increased risk of cardiovascular death in a general outpatient population. With clarithromycin, we observed a transient increased risk during days 0-7 after treatment start, which corresponds to the period of active treatment. This association was absent in later time periods, which is consistent with no long-term toxicity resulting in cardiovascular death.

Concomitant use of low-dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis.

PURPOSE: Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis. METHODS: The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n = 21 536) and control episodes of use of methotrexate alone (n = 21 725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores. RESULTS: During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia. CONCLUSIONS: Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed.

Ondansetron in pregnancy and risk of adverse fetal outcomes.

BACKGROUND: Ondansetron is frequently used to treat nausea and vomiting during pregnancy, but the safety of this drug for the fetus has not been well studied. METHODS: We investigated the risk of adverse fetal outcomes associated with ondansetron administered during pregnancy. From a historical cohort of 608,385 pregnancies in Denmark, women who were exposed to ondansetron and those who were not exposed were included, in a 1:4 ratio, in propensity-score-matched analyses of spontaneous abortion (1849 exposed women vs. 7396 unexposed women), stillbirth (1915 vs. 7660), any major birth defect (1233 vs. 4932), preterm delivery (1792 vs. 7168), and birth of infants at low birth weight and small for gestational age (1784 vs. 7136). In addition, estimates were adjusted for hospitalization for nausea and vomiting during pregnancy (as a proxy for severity) and the use of other antiemetics. RESULTS: Receipt of ondansetron was not associated with a significantly increased risk of spontaneous abortion, which occurred in 1.1% of exposed women and 3.7% of unexposed women during gestational weeks 7 to 12 (hazard ratio, 0.49; 95% confidence interval [CI], 0.27 to 0.91) and in 1.0% and 2.1%, respectively, during weeks 13 to 22 (hazard ratio, 0.60; 95% CI, 0.29 to 1.21). Ondansetron also conferred no significantly increased risk of stillbirth (0.3% for exposed women and 0.4% for unexposed women; hazard ratio, 0.42; 95% CI, 0.10 to 1.73), any major birth defect (2.9% and 2.9%, respectively; prevalence odds ratio, 1.12; 95% CI, 0.69 to 1.82), preterm delivery (6.2% and 5.2%; prevalence odds ratio, 0.90; 95% CI, 0.66 to 1.25), delivery of a low-birth-weight infant (4.1% and 3.7%; prevalence odds ratio, 0.76; 95% CI, 0.51 to 1.13), or delivery of a small-for-gestational-age infant (10.4% and 9.2%; prevalence odds ratio, 1.13; 95% CI, 0.89 to 1.44). CONCLUSIONS: Ondansetron taken during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes. (Funded by the Danish Medical Research Council.).

Use of azithromycin and death from cardiovascular causes.

BACKGROUND: Azithromycin use is associated with an increased risk of death from cardiovascular causes among patients at high baseline risk. Whether azithromycin confers a similar risk in the unselected general population is unknown. METHODS: We conducted a nationwide historical cohort study involving Danish adults (18 to 64 years of age), linking registry data on filled prescriptions, causes of death, and patient characteristics for the period from 1997 through 2010. We estimated rate ratios for death from cardiovascular causes, comparing 1,102,050 episodes of azithromycin use with no use of antibiotic agents (matched in a 1:1 ratio according to propensity score, for a total of 2,204,100 episodes) and comparing 1,102,419 episodes of azithromycin use with 7,364,292 episodes of penicillin V use (an antibiotic with similar indications; analysis was conducted with adjustment for propensity score). RESULTS: The risk of death from cardiovascular causes was significantly increased with current use of azithromycin (defined as a 5-day treatment episode), as compared with no use of antibiotics (rate ratio, 2.85; 95% confidence interval [CI], 1.13 to 7.24). The analysis relative to an antibiotic comparator included 17 deaths from cardiovascular causes during current azithromycin use (crude rate, 1.1 per 1000 person-years) and 146 during current penicillin V use (crude rate, 1.5 per 1000 person-years). With adjustment for propensity scores, current azithromycin use was not associated with an increased risk of cardiovascular death, as compared with penicillin V (rate ratio, 0.93; 95% CI, 0.56 to 1.55). The adjusted absolute risk difference for current use of azithromycin, as compared with penicillin V, was -1 cardiovascular death (95% CI, -9 to 11) per 1 million treatment episodes. CONCLUSIONS: Azithromycin use was not associated with an increased risk of death from cardiovascular causes in a general population of young and middle-aged adults. (Funded by the Danish Medical Research Council.).

Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth.

IMPORTANCE: Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information. OBJECTIVE: To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group. EXPOSURES: Filled prescriptions for oral fluconazole were obtained from the National Prescription Register. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression. RESULTS: Among 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]). CONCLUSIONS AND RELEVANCE: In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.

The use of valproic acid and multiple sclerosis.

BACKGROUND: Animal studies have suggested that drugs inhibiting the enzyme histone deacetylase might have a beneficial effect on multiple sclerosis (MS). Valproic acid (VPA), an anti-epileptic drug, is the only widely used human drug with a histone deacetylase inhibitory effect. OBJECTIVE: The objective of this paper is to examine if VPA use is associated with a reduced risk of MS. METHODS: We conducted a propensity score-matched cohort study in the period 1997-2011 linking nationwide register data on filled VPA prescriptions, MS cases, and several covariates. The VPA users were matched on propensity scores in a 1:4 ratio with non-users of VPA. Incidence rates of MS were compared among VPA users and non-users of VPA using Cox regression to estimate hazard ratios (HRs). RESULTS: Among 16 028 ever-users of VPA and 54 172 non-users, 18 and 26 cases of MS were identified, respectively. Neither current VPA users nor recent users of VPA, who had ceased VPA treatment within the last year, were at a reduced risk of MS compared with non-users of VPA (HR = 1.30 (95% confidence interval, 0.44-3.80), n = 4, and HR = 1.22 (0.28-5.32), n = 2, respectively). Similarly, in an intention-to-treat analysis, ever-users of VPA were not at reduced risk of MS (HR = 2.41 (1.32-4.43), n = 18). CONCLUSION: In the first human study addressing a possible beneficial effect of VPA use on the risk of MS, we found no support for a protective effect. However, given the wide confidence intervals, only large effects can be ruled out with sufficient certainty.

Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system.

IMPORTANCE: Case reports have suggested a link between human papillomavirus (HPV) vaccination and development of multiple sclerosis and other demyelinating diseases. OBJECTIVE: To investigate if quadrivalent HPV (qHPV) vaccination is associated with an increased risk of multiple sclerosis and other demyelinating diseases. DESIGN, SETTING, AND PARTICIPANTS: Using nationwide registers we identified a cohort of all females aged 10 years to 44 years in Denmark and Sweden, followed up from 2006 to 2013, information on qHPV vaccination, and data on incident diagnoses of multiple sclerosis and other demyelinating diseases. The primary analysis used a cohort design including vaccinated and unvaccinated study participants. A secondary analysis used a self-controlled case-series design including only cases. Both analyses used a 2-year risk period following vaccination. EXPOSURES: Information on qHPV vaccination was obtained through the national vaccination and prescription registers. MAIN OUTCOMES AND MEASURES: The primary outcomes were multiple sclerosis and a composite end point of other demyelinating diseases. Incidence rate ratios were estimated using Poisson regression, comparing rates of events in the 2-year risk periods following vaccination and in unvaccinated time periods. RESULTS: The study included 3,983,824 females, among whom 789,082 received a total of 1,927,581 qHPV vaccine doses. During follow-up, 4322 multiple sclerosis cases and 3300 cases of other demyelinating diseases were identified, of which 73 and 90, respectively, occurred within the risk period. In the cohort analysis, there was no increased risk of multiple sclerosis (crude incidence rates, 6.12 events/100,000 person-years [95% CI, 4.86-7.69] and 21.54 events/100,000 person-years [95% CI, 20.90-22.20] for the vaccinated and unvaccinated periods; adjusted rate ratio, 0.90 [95% CI, 0.70-1.15]) or other demyelinating diseases (crude incidence rates, 7.54 events/100,000 person-years [95% CI, 6.13-9.27] and 16.14 events/100,000 person-years [95% CI, 15.58-16.71]; adjusted rate ratio, 1.00 [95% CI, 0.80-1.26]) associated with qHPV vaccination. Similarly, no increased risk was found using the self-controlled case-series design (multiple sclerosis: incidence ratio, 1.05 [95% CI, 0.79-1.38]; other demyelinating diseases: incidence ratio, 1.14 [95% CI, 0.88-1.47]). CONCLUSIONS AND RELEVANCE: In this study with nationwide coverage of 2 Scandinavian countries, qHPV vaccination was not associated with the development of multiple sclerosis or other demyelinating diseases. These findings do not support concerns about a causal relationship between qHPV vaccination and demyelinating diseases.

Use of strontium ranelate and risk of acute coronary syndrome: cohort study.

BACKGROUND: A recent pooled analysis of randomised trials found an increased risk of myocardial infarction with use of the antiosteoporotic drug strontium ranelate. We conducted a nationwide cohort study in Denmark, 2005-2011, to investigate the risk of acute coronary syndrome among postmenopausal women treated with strontium ranelate. METHODS: The study involved two analytic setups. The first analysis included new users of either strontium ranelate (n=1798) or one of the two first-line bisphosphonates in Denmark (alendronate and risedronate; n=65 236). The second analysis included patients who had first been treated with a first-line bisphosphonate and subsequently switched to either strontium ranelate (n=1219) or ibandronate (n=2290). The primary outcome was acute coronary syndrome (unstable angina or myocardial infarction). The secondary outcome was any-cause mortality. Cox regression was used to estimate HRs, with adjustment using a disease risk score. RESULTS: Compared with use of alendronate/risedronate, use of strontium was not associated with significantly increased risk of acute coronary syndrome (rate per 1000 person-years 5.7 for strontium vs 6.3 for alendronate/risedronate; adjusted HR 0.89, 95% CI 0.52 to 1.55) or any-cause mortality (adjusted HR 0.96, 95% CI 0.76 to 1.21). In the analysis of switchers, strontium was not associated with significantly increased risk of acute coronary syndrome (rate per 1000 person-years 9.9 for strontium vs 9.9 for ibandronate; adjusted HR 1.00, 95% CI 0.49 to 2.05) or of any-cause mortality (adjusted HR 1.45, 95% CI 0.95 to 2.21). INTERPRETATION: These real-world data of antiosteoporotic drug users do not support a significant association between use of strontium ranelate and acute coronary syndrome.

Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease.

IMPORTANCE: A Cochrane review and network meta-analysis concluded that there is need for more research on adverse effects, including cancer, after treatment with tumor necrosis factor α (TNF-α) antagonists and that national registries and large databases would provide relevant sources of data to evaluate these effects. OBJECTIVE: To investigate whether patients with inflammatory bowel disease (IBD) exposed to TNF-α antagonists were at increased risk of developing cancer. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study in Denmark, 1999-2012. Participants were 56,146 patients 15 years or older with IBD identified in the National Patient Registry, of whom 4553 (8.1%) were exposed to TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry. MAIN OUTCOMES AND MEASURES: Rate ratios (RRs) for incident cancer (overall and site-specific) comparing TNF-α antagonist users and nonusers, estimated using Poisson regression adjusted for age, calendar year, disease duration, propensity scores, and use of other IBD medications. RESULTS: During 489,433 person-years of follow-up (median, 9.3 years [interquartile range, 4.2-14.0]), 81 of 4553 patients exposed to TNF-α antagonists (1.8%) (median follow-up, 3.7 years [interquartile range, 1.8-6.0]) and 3465 of 51,593 unexposed patients (6.7%) developed cancer, yielding a fully adjusted RR of 1.07 (95% CI, 0.85-1.36). There was no significantly increased risk of cancer in analyses according to time since first TNF-α antagonist exposure (less than 1 year: RR, 1.10 [95% CI, 0.67-1.81]; 1 to less than 2 years: RR, 1.22 [95% CI, 0.77-1.93]; 2 to less than 5 years: RR, 0.82 [95% CI, 0.54-1.24]; 5 or more years: RR, 1.33 [95% CI, 0.88-2.03]) and in analyses according to the number of TNF-α antagonist doses received (1 to 3 doses: RR, 1.02 [95% CI, 0.71-1.47]; 4 to 7 doses: RR, 0.89 [95% CI, 0.55-1.42]; 8 or more doses: RR, 1.29 [95% CI, 0.90-1.85]). No site-specific cancers were in significant excess in fully adjusted models. CONCLUSIONS AND RELEVANCE: In this Danish nationwide study, exposure to TNF-α antagonists among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years among those exposed. An increased risk associated with longer-term accumulated doses and follow-up cannot be excluded.

Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study.

OBJECTIVE: To investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer. DESIGN: Scandinavian cohort study. SETTING: Denmark, Norway, and Sweden, 2007-21. PARTICIPANTS: Patients who started GLP1 receptor agonist treatment were compared with patients who started dipeptidyl peptidase 4 (DPP4) inhibitor treatment, and in an additional analysis, patients who started sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. MAIN OUTCOME MEASURES: Thyroid cancer identified from nationwide cancer registers. An active-comparator new user study design was used to minimise risks of confounding and time related biases from using real world studies of drug effects. Cox regression was used to estimate hazard ratios, controlling for potential confounders with propensity score weighting. RESULTS: The mean follow-up time was 3.9 years (standard deviation 3.5 years) in the GLP1 receptor agonist group and 5.4 years (standard deviation 3.5 years) in the DPP4 inhibitor group. 76 of 145 410 patients (incidence rate 1.33 events per 10 000 person years) treated with GLP1 receptor agonists and 184 of 291 667 patients (incidence rate 1.46 events per 10 000 person years) treated with DPP4 inhibitors developed thyroid cancer. GLP1 receptor agonist use was not associated with increased risk of thyroid cancer (hazard ratio 0.93, 95% confidence interval 0.66 to 1.31; rate difference -0.13, 95% confidence interval -0.61 to 0.36 events per 10 000 person years). The hazard ratio for medullary thyroid cancer was 1.19 (0.37 to 3.86). In the additional analysis comparing the GLP1 receptor agonist group with the SGLT2 inhibitor group, the hazard ratio for thyroid cancer was 1.16 (0.65 to 2.05). CONCLUSIONS: In this large cohort study using nationwide data from three countries, GLP1 receptor agonist use was not associated with a substantially increased risk of thyroid cancer over a mean follow-up of 3.9 years. In the main analysis comparing GLP1 receptor agonists with DPP4 inhibitors, the upper limit of the confidence interval was consistent with no more than a 31% increase in relative risk.

Background incidence rates of health outcomes in populations at risk for Lyme disease using US administrative claims data.

BACKGROUND: Background incidence rates (IRs) of health outcomes in Lyme disease endemic regions are useful to contextualize events reported during Lyme disease vaccine clinical trials or post-marketing. The objective of this study was to estimate and compare IRs of health outcomes in Lyme disease endemic versus non-endemic regions in the US during pre-COVID and COVID era timeframes. METHODS: IQVIA PharMetrics® Plus commercial claims database was used to estimate IRs of 64 outcomes relevant to vaccine safety monitoring in the US during January 1, 2017-December 31, 2019 and January 1, 2020-December 31, 2021. Analyses included all individuals aged ≥ 2 years with ≥ 1 year of continuous enrollment. Outcomes were defined by International Classification of Diseases Clinical Modification, 10th Revision (ICD-10-CM) diagnosis codes. IRs and 95 % confidence intervals (CIs) were calculated for each outcome and compared between endemic vs. non-endemic regions, and pre-COVID vs. COVID era using IR ratios (IRR). RESULTS: The study population included 8.7 million (M) in endemic and 27.8 M in non-endemic regions. Mean age and sex were similar in endemic and non-endemic regions. In both study periods, the IRs were statistically higher in endemic regions for anaphylaxis, meningoencephalitis, myocarditis/pericarditis, and rash (including erythema migrans) as compared with non-endemic regions. Conversely, significantly lower IRs were observed in endemic regions for acute kidney injury, disseminated intravascular coagulation, heart failure, myelitis, myopathies, and systemic lupus erythematosus in both study periods. Most outcomes were statistically less frequent during the COVID-era. CONCLUSION: This study identified potential differences between Lyme endemic and non-endemic regions of the US in background IRs of health conditions during pre-COVID and COVID era timeframes to inform Lyme disease vaccine safety monitoring. These regional and temporal differences in background IRs should be considered when contextualizing possible safety signals in clinical trials and post-marketing of a vaccine targeted at Lyme disease prevention.