Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial.

BACKGROUND: ONWARDS 6 compared the efficacy and safety of once-weekly subcutaneous insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with type 1 diabetes. METHODS: This 52-week (26-week main phase plus a 26-week safety extension), randomised, open-label, treat-to-target, phase 3a trial was done at 99 sites across 12 countries. Adults with type 1 diabetes (glycated haemoglobin [HbA1c] <10·0% [86 mmol/mol]) were randomly assigned (1:1) to once-weekly icodec or once-daily degludec, both in combination with insulin aspart (two or more daily injections). The primary endpoint was change in HbA1c from baseline to week 26, tested for non-inferiority (0·3 percentage point margin) in all randomly assigned participants. This trial is registered with ClinicalTrials.gov, NCT04848480, and is now complete. FINDINGS: Between April 30 and Oct 15, 2021, of 655 participants screened, 582 participants were randomly assigned to icodec (n=290) or degludec (n=292). At week 26, from baseline values of 7·59% (icodec) and 7·63% (degludec), estimated mean changes in HbA1c were -0·47 percentage points and -0·51 percentage points, respectively (estimated treatment difference 0·05 percentage points [95% CI -0·13 to 0·23]), confirming non-inferiority of icodec to degludec (p=0·0065). Overall rate of combined clinically significant or severe hypoglycaemia (baseline to week 26) was statistically significantly higher with icodec than degludec (19·9 vs 10·4 events per patient-year of exposure; estimated rate ratio 1·9 [95% CI 1·5 to 2·3]; p<0·0001). The rate was also statistically significantly higher with icodec than degludec when evaluated over 57 weeks (52 weeks plus a 5-week follow-up period). 39 serious adverse events were reported in 24 (8%) participants receiving icodec, and 25 serious adverse events were reported in 20 (7%) participants receiving degludec. One participant in the icodec group died; this was judged unlikely to be due to the trial product. INTERPRETATION: In adults with type 1 diabetes, once-weekly icodec showed non-inferiority to once-daily degludec in HbA1c reduction at week 26, with statistically significantly higher rates of combined clinically significant or severe hypoglycaemia. For icodec, time below 3·0 mmol/L (<54 mg/dL) was at the threshold of the internationally recommended target (<1%) during weeks 22-26 and below target during weeks 48-52. FUNDING: Novo Nordisk.

Birth outcomes after prenatal exposure to antiepileptic drugs--a population-based study.

OBJECTIVE: We studied the potential impact of antiepileptic drugs (AEDs) on fetal growth and gestational age at birth. METHODS: In the Danish Medical Birth Registry, we identified all pregnancies with birth outcomes from 1997 to 2008 and linked with data from the Danish National Prescription Register. We used binomial regression to study preterm birth (<37 weeks), low birth weight (<2,500 g), and small for gestational age (SGA), adjusted for potential confounding factors including maternal age, smoking, substance abuse, cohabitation, income, education, and parity. RESULTS: We identified 679,762 singletons, and 2,928 (0.4%) of these had been exposed to AEDs. Exposure to AEDs was associated with a risk of preterm birth (adjusted risk ratio (aRR) 1.32; 95% confidence interval [CI] 1.16-1.50) when compared to unexposed children. However, when stratifying on maternal epilepsy, there was no association between AED exposure and preterm birth in offspring of women with epilepsy (aRR 1.00; 95% CI 0.82-1.21), whereas there was a risk associated with AED exposure in offspring of women without epilepsy (aRR 1.56; 95% CI 1.27-1.92). AED exposure was associated with a risk of being born with low birth weight (aRR 1.40; 95% CI 1.22-1.60) both for children born of women with epilepsy (aRR 1.32; 95% CI 1.06-1.63) and children born of women without epilepsy (aRR 1.61; 95% CI 1.28-2.02). The risk of being born SGA associated with AED exposure (aRR 1.21; 95% CI 1.10-1.34) was found both in offspring of women with epilepsy (aRR 1.19; 95% CI 1.02-1.37) and without epilepsy (aRR 1.21; 95% CI 1.01-1.45). SIGNIFICANCE: Prenatal AED exposure was associated with low birth weight and risk of being born SGA, but only with preterm birth among women without epilepsy.

Early treatment with talk therapy or antidepressants in severely bereaved people and risk of suicidal behavior and psychiatric illness: an instrumental variable analysis.

PURPOSE: Losing a loved one to death is a common and natural life-course experience. Still, bereavement has been associated with an increased risk of suicidal behavior and psychiatric hospitalization and little is known of how to counter these adverse events. We aimed to study the effect of early treatment in primary care with talk therapy (TT) or antidepressants (AD) in severely bereaved people. METHODS: We conducted a population-based cohort study including 207,435 adult Danes who experienced a severe loss in 1996-2013. We compared treatment and no treatment with either of the two treatment regimens within 6 months after the loss. The main outcome was a serious mental health condition (defined as suicide, deliberate self-harm, or psychiatric hospitalization) occurring >6 months after bereavement. Adjusted risk differences (RDs) 2 years after bereavement were calculated using both standard regression analysis and instrumental variable analysis (IVA) in which estimated physician preferences for treatment served as instruments. RESULTS: The standard adjusted regression analysis showed a higher risk of developing a serious mental health condition associated with both TT (RD, 7.1; 95% CI, 5.0 to 9.1 per 1000 people) and AD (RD, 30.1; 95% CI, 25.7 to 34.6 per 1000 people). The IVA, which was used to control for unmeasured confounding, showed that TT was associated with a lower risk of a serious mental health condition (RD, -17.1; 95% CI, -30.7 to -3.5 per 1000 people), whereas the results were inconclusive for AD (RD, -8.6; 95% CI, -62.6 to 45.4 per 1000 people). CONCLUSION: This study suggests that early treatment with TT is associated with reduced long-term risk of serious mental health conditions in severely bereaved people. No clear benefit or harm of treatment with AD after bereavement was ascertained since the statistical precision was low.

Algorithm linking patients and general practices in Denmark using the Danish National Health Service Register.

BACKGROUND: The patient list system in Denmark assigns virtually all residents to a general practice. Nevertheless, historical information on this link between patient and general practice is not readily available for research purposes. OBJECTIVES: To develop, implement, and evaluate the performance of an algorithm linking individual patients to their general practice by using information from the Danish National Health Service Register and the Danish Civil Registration System. MATERIALS AND METHODS: The National Health Service Register contains information on all services provided by general practitioners from 1990 and onward. On the basis of these data and information on migration history and death obtained from the Civil Registration System, we developed an algorithm that allocated patients to a general practice on a monthly basis. We evaluated the performance of the algorithm between 2002 and 2007. During this time period, we had access to information on the link between patients and general practices. Agreement was assessed by the proportion of months for which the algorithm allocated patients to the correct general practice. We also assessed the proportion of all patients in the patient list system for which the algorithm was able to suggest an allocation. RESULTS: The overall agreement between algorithm and patient lists was 98.6%. We found slightly higher agreement for women (98.8%) than for men (98.4%) and lower agreement in the age group 18-34 years (97.1%) compared to all other age groups (≥98.6%). The algorithm had assigned 83% of all patients in the patient list system after 1 year of follow-up, 91% after 2 years of follow-up, and peaked at 94% during the fourth year. CONCLUSION: We developed an algorithm that enables valid and nearly complete linkage between patients and general practices. The algorithm performs better in subgroups of patients with high health care needs. The algorithm constitutes a valuable tool for primary health care research.

Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study.

OBJECTIVES: It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring. SETTING: Population-based study using health registers in Denmark. PARTICIPANTS: We identified all 677 021 singletons born in Denmark from 1997 to 2008 and linked the Apgar score from the Medical Birth Register with information on the women's prescriptions for AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the child. Results were adjusted for smoking and maternal age. RESULTS: Among 2906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤7 as compared with 8797 (1.3%) children among 674 115 pregnancies unexposed to AEDs (adjusted relative risk (aRR)=1.41 (95% CI 1.07 to 1.85). When analyses were restricted to the 2215 children born of mothers with epilepsy, the aRR of having a low Apgar score associated with AED exposure was 1.34 (95% CI 0.90 to 2.01) When assessing individual AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR=1.86 (95% CI 1.01 to 3.42)), valproic acid (RR=1.85 (95% CI 1.04 to 3.30)) and topiramate (RR=2.97 (95% CI 1.26 to 7.01)) when compared to unexposed children. CONCLUSIONS: Prenatal exposure to AEDs was associated with increased risk of being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with individual AEDs indicate that the increased risk is not a class effect, but that there may be particularly high risks of a low Apgar score associated with certain AEDs.

Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy.

OBJECTIVE: To determine if prenatal exposure to methylphenidate (MPH) or atomoxetine (ATX) increases the risk of adverse pregnancy outcomes in women with attention deficit/hyperactivity disorder (ADHD). MATERIALS AND METHODS: This was a population-based cohort study of all pregnancies in Denmark from 1997 to 2008. Information on use of ADHD medication, ADHD diagnosis, and pregnancy outcomes was obtained from nationwide registers. RESULTS: We identified 989,932 pregnancies, in which 186 (0.02%) women used MPH/ATX and 275 (0.03%) women had been diagnosed with ADHD but who did not take MPH/ATX. Our reference pregnancies had no exposure to MPH/ATX and no ADHD diagnosis. Exposure to MPH/ATX was associated with an increased risk of spontaneous abortion (SA; ie, death of an embryo or fetus in the first 22 weeks of gestation) (adjusted relative risk [aRR] 1.55, 95% confidence interval [CI] 1.03-2.36). The risk of SA was also increased in pregnancies where the mother had ADHD but did not use MPH/ATX (aRR 1.56, 95% CI 1.11-2.20). The aRR of Apgar scores <10 was increased among exposed women (aRR 2.06, 95% CI 1.11-3.82) but not among unexposed women with ADHD (aRR 0.99, 95% CI 0.48-2.05). CONCLUSION: MPH/ATX was associated with a higher risk of SA, but our study indicated that it may at least partly be explained by confounding by indication. Treatment with MPH/ATX was however associated with low Apgar scores <10, an association not found among women with ADHD who did not use MPH/ATX.

Risk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy.

BACKGROUND: Antipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth. METHODS: In a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively. RESULTS: Women exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19). CONCLUSIONS: The increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.

Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study.

OBJECTIVE: To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. DESIGN: Population based cohort study. SETTING: Register based study in Denmark, 1997-2008. PARTICIPANTS: 983,305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. MAIN OUTCOME MEASURES: Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. RESULTS: Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). CONCLUSION: Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.

Prenatal antidepressant exposure and risk of spontaneous abortion - a population-based study.

PURPOSE: To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy. METHODS: From the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression. RESULTS: Of the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10-1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80-1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population. CONCLUSION: We identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.