The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D. METHODS: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes. RESULTS: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression. CONCLUSION: FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial.

AIM: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. MATERIALS AND METHODS: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 ). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed. RESULTS: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m2 , glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants. CONCLUSION: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.

Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses.

INTRODUCTION: The efficacy and safety of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, were investigated in patients with type 2 diabetes (T2D) in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups. METHODS: Data from patients in the PIONEER 3-5, 7 and 8 trials receiving once-daily oral semaglutide (14 mg/flexibly dosed) or a comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg) were analysed for efficacy (glycated haemoglobin [HbA1c] and body weight changes from baseline to planned end of treatment) and safety outcomes. Patients were grouped according to background medication (metformin, sulphonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, insulin, or combinations thereof). Efficacy outcomes were analysed using the trial product estimand (which assumes that patients remained on the trial product without rescue medication use). A separate analysis by background insulin regimen (basal, premixed or basal-bolus) was done for PIONEER 8 using the treatment policy estimand (regardless of trial product discontinuation or rescue medication use). Safety outcomes were analysed descriptively for all patients. RESULTS: In total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Baseline characteristics were generally similar across background medication subgroups within each trial. Diabetes duration tended to be longer in patients receiving more background medications. Greater HbA1c and body weight reductions were seen across background medication subgroups with oral semaglutide (changes from baseline: - 1.0 to - 1.5% and - 2.2 to - 5.0 kg, respectively) than with comparators (except for similar HbA1c reductions vs liraglutide). There were no statistically significant interactions by treatment and background medication subgroup for change in HbA1c or body weight except for change in HbA1c (background insulin vs insulin plus metformin) in PIONEER 8 (p = 0.0408). Changes in HbA1c and body weight were generally similar across insulin regimen subgroups, without significant treatment interactions by subgroup, and the total daily insulin dose was decreased for patients receiving oral semaglutide. The incidence of adverse events was generally similar in background medication subgroups. CONCLUSION: Oral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02607865 (PIONEER 3), NCT02863419 (PIONEER 4), NCT02827708 (PIONEER 5), NCT02849080 (PIONEER 7) and NCT03021187 (PIONEER 8).

Trends in the survival of patients diagnosed with cancer in the Nordic countries 1964-2003 followed up to the end of 2006. Material and methods.

UNLABELLED: Comparable data on cancer incidence and mortality in Denmark, Finland, Iceland, Norway, and Sweden are available for analysis through a collaboration of the national Cancer Registries via the NORDCAN website (http://ancr.nu). In the continued spirit of Nordic collaborative research, a number of studies examining trends in cancer survival are published in this journal. MATERIAL AND METHODS: The data were divided into eight 5-year periods by sex in five Nordic countries. Age-standardised 5-year relative survival ratios and excess mortality rates in the short-term (first month and 1-3 months following diagnosis), and the long-term (2-5 years after diagnosis) were calculated, as were age-specific 5-year relative survival using cohort-survival methods. A hybrid method combining the cohort and period methods was used for the period 1999-2003 as not all patients were followed for five years. Age-standardisation used the International Cancer Survival Standard, and calculation of expected deaths used country-specific population mortality rates. RESULTS: The data series constitutes 3 360 397 tumours among 3 160 802 patients followed up for death through 2006 for 39 different cancer sites diagnosed in the years 1964-2003. The paper describes the data, exclusions and imputations, design and analysis, age structure and standardisation procedures, follow-up, and case-mix adjustment methods. CONCLUSION: The strengths of this study include the overall comparability and quality of the data, the national coverage, and the length of the time series. Collecting and analysing data from the five Nordic countries for 39 different cancer sites over 40 years in a systematised and comparable way is a major undertaking. A thorough description of the analyses, definitions and exclusions in the survival study, supplemented with corresponding information on cancer incidence and mortality is needed for appropriate interpretation and comparison between countries, and between and within cancer sites. This information must be made available to provide appropriate interpretation of the site-specific results.

Trends in the survival of patients diagnosed with breast cancer in the Nordic countries 1964-2003 followed up to the end of 2006.

BACKGROUND: Breast cancer is the leading cancer among women worldwide in terms of both incidence and mortality. European patients have generally high 5-year relative survival ratios, and the Nordic countries, except for Denmark, have ratios among the highest. MATERIAL AND METHODS: Based on the NORDCAN database we present trends in age-standardised incidence and mortality rates of invasive breast cancer in the Nordic countries, alongside 5- and 10-year relative survival for the period of diagnosis 1964-2003 followed up to the end of 2006. Excess mortality rates are also provided for varying follow-up intervals after diagnosis. The analysis is confined to invasive breast cancer in Nordic women. RESULTS: Incidence increased rapidly in all five countries, whereas mortality remained almost unchanged. Both incidence and mortality rates were highest in Denmark. Between 1964 and 2003 both 5- and 10-year relative survival increased by 20-30 percentage points in all countries, and 10-year survival remained around 10 percentage points lower than 5-year survival. Relative survival was lowest in Denmark throughout the period, with a 5-year survival of 79% for years 1999-2003, but 83-87% in the other countries. From 1964 the youngest women had the highest survival ratios up until the introduction of screening, when a shift occurred towards higher survival among age groups 50-59 and 60-69 in each country, except for Denmark. Excess death rates during the first months after diagnosis were highest in Denmark. CONCLUSION: Breast cancer survival is high and rising in the Nordic countries, and probably relates to the early implementation of organised mammography screening in each country except Denmark and a high and relatively uniform standard of living, diagnosis and treatment. Denmark stands out with higher mortality and poorer survival. The major determinants may include a failure to instigate national breast screening and a greater co-morbidity resulting from a higher prevalence of both tobacco smoking and alcohol consumption.

Survival of patients diagnosed with cancer in the Nordic countries up to 1999-2003 followed to the end of 2006. A critical overview of the results.

UNLABELLED: Differences in Nordic cancer patient survival observed today originate from the 1970s, but were first identified in a mortality prediction from 1995. This paper provides timely comparisons of survival using NORDCAN, a database with comparable information from the Nordic cancer registries. Elucidation of the differences is important when monitoring cancer care generally and evaluating the impact of cancer plans. MATERIAL AND METHODS: The NORDCAN database 1964-2003 with follow-up for death through 2006, was used to analyse incidence, mortality, and survival for all NORDCAN cancer sites. We analysed 5-year relative survival and excess mortality rates in the first three months and 2-5 years after diagnosis. RESULTS: The time trends in survival 1989-2003 were largely similar between the Nordic countries with increases in 14 sites among men and 16 among women. In all countries the excess mortality rates were highest in the first three months after diagnosis, but decreased to similar levels across all countries 2-5 years after diagnosis. Comparing countries excess mortality was highest in Denmark irrespective of follow-up period. Lower survival was observed for Danish cancer patients in 23 of the 33 cancer sites in men and 26 of 35 sites in women. Low and similar levels of survival were observed for cancers of the oesophagus, lung, liver and pancreas, while an 8-10 percentage point difference in survival was found between countries for colorectal cancer. CONCLUSION: The notable differences in Nordic cancer patient survival can be linked to national variations in risk factors, co-morbidity, and the implementation of screening. Improved treatment and primary prevention, in particular the targeting of tobacco and alcohol use, is required to improve cancer control. The recently-initiated cancer plans in Denmark and Norway are yet to show an observable effect on the corresponding cancer survival.

Trends in survival of patients diagnosed with cancer of the digestive organs in the Nordic countries 1964-2003 followed up to the end of 2006.

UNLABELLED: Cancers of the digestive organs (including the oesophagus, stomach, small intestine, colon, rectum and anus, liver, gallbladder, and pancreas) constitute one-fifth of all cancer cases in the Nordic countries and is a group of diseases with diverse time trends and varying consequences for public health. In this study we examine trends in relative survival in relation to the corresponding incidence and mortality rates in the Nordic countries during the period 1964-2003. MATERIAL AND METHODS: Data were retrieved from the NORDCAN database for the period 1964 to 2003, grouped into eight 5-year periods of diagnosis. The patients were followed up until the end of 2006. Analysis comprised trends in 5-year relative survival, excess mortality and age-specific relative survival. RESULTS: Survival following cancers of the colon and rectum has increased continuously over the observed period, yet Danish patients fall behind those in the other Nordic countries. The largest inter-country variation is seen for the rare cancers in the small intestine. There has been little increase in prognosis for patients diagnosed with cancers of the liver, gallbladder or pancreas; 5-year survival is generally below 15%. Survival also remains consistently low for patients with oesophageal cancer, while minor increases in survival are seen among stomach cancer patients in all countries except Denmark. The concomitant incidence and mortality rates of stomach cancer have steadily decreased in each Nordic country at least since 1964. CONCLUSION: While the site-specific variations in mortality and survival largely reflect the extent of changing and improving diagnostic and clinical practices, the incidence trends highlight the importance of risk factor modification. Alongside the ongoing clinical advances, effective primary prevention measures, including the control of alcohol and tobacco consumption as well as changing dietary pattern, will reduce the incidence and mortality burden of digestive cancers in the Nordic countries.

Trends in the survival of patients diagnosed with malignant melanoma of the skin in the Nordic countries 1964-2003 followed up to the end of 2006.

UNLABELLED: A previous Nordic study showed a marked and steady increase in the age-adjusted 5-year relative survival of skin melanoma patients diagnosed during the period 1958 through 1987. Males had considerably poorer survival than females. MATERIAL AND METHODS: Using the NORDCAN database, we studied relative survival and excess mortality of patients diagnosed with melanoma of the skin in the Nordic countries 1964-2003 followed up to the end of 2006. These were contrasted with concomitant trends in incidence and mortality. RESULTS: The overall incidence of melanoma almost quadrupled, but there was considerable variation in the trends in the five countries. Mortality was low but doubled during the study period. Survival ratios increased steadily to between 80% and 90% for patients diagnosed in 1999-2003. Swedish patients had consistently higher survival, whereas Danish patients had the highest excess death rates the first three months after diagnosis up until 1990, but thereafter, rates reached a similar low level to that observed in the other Nordic countries. The survival of Nordic women is still higher than that of men, but the difference has diminished, while the mortality rates among men are becoming increasingly higher relative to those for women among individuals 50 years and older. In younger individuals, mortality rates are similar in the two sexes, and declining. CONCLUSIONS: Nordic patient survival following melanoma diagnosis is generally high and has been steadily increasing in the last decades. Differences in incidence between the five countries are more pronounced than the differences in survival. The strong upward trends in incidence and survival may mainly be the result of extensive changes in sunbathing habits or other UV exposure and, more recently, of an increasing awareness by the medical community and the public concerning early detection of melanoma of the skin.

Trends in the survival of patients diagnosed with malignant neoplasms of lymphoid, haematopoietic, and related tissue in the Nordic countries 1964-2003 followed up to the end of 2006.

BACKGROUND: Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma, and acute and other leukaemias constitute about 7% of the overall cancer incidence and 8% of cancer mortality in the Nordic countries. The aim of this study is to describe and interpret the trends in relative survival and excess mortality in the five Nordic populations among these patients. MATERIAL AND METHODS: Using the NORDCAN database 1964-2003, we estimated age-standardised incidence and mortality rates, 5-year relative survival, and excess mortality rates for varying follow-up periods, and age-specific 5-year relative survival by country, sex, and 5-year diagnostic period. RESULTS: Taking into account classification and registration problems in the earlier periods, the patterns of incidence, mortality, and survival are fairly similar between the countries within each cancer form studied. High 5-year relative survival ratios of over 80% were seen in the most recent period 1999-2003 for Hodgkin lymphoma, between 50 and 60% for Non-Hodgkin lymphoma, 38-49% for acute leukaemia and 60-73% for other leukaemia. The variations were between 28 and 41% for multiple myeloma. Danish patients diagnosed with these malignancies tend to fare slightly worse than their Nordic neighbours, with excess mortality rates marginally higher one to three months after diagnosis. CONCLUSION: Although the recent trends and absolute levels of incidence, mortality and survival for the lympho-haematopoietic malignancies are similar, the consistently lower survival of Danish patients--irrespective of type of malignancy--points to an impact of co-morbidity related lifestyle factors, which may negatively affect the chemotherapy and radiation offered as standard treatments for these diseases.

Trends in survival of patients diagnosed with cancers of the brain and nervous system, thyroid, eye, bone, and soft tissues in the Nordic countries 1964-2003 followed up until the end of 2006.

BACKGROUND: Diagnoses of cancer of the brain, thyroid, eye, bone, and soft tissues are categorised by heterogeneity in disease frequency, survival, aetiology and prospects for curative therapy. In this paper, temporal trends in patient survival in the Nordic countries are considered. MATERIAL AND METHODS: Age-standardised incidence and mortality rates, 5-year relative survival, and excess mortality rates for varying follow-up periods are presented, as are age-specific 5-year relative survival by country, sex and 5-year diagnostic period. RESULTS: Brain cancer incidence rates have been rising but mortality has been relatively stable, with 5-year survival uniformly increasing from the early-1970s, particularly in younger patients. Five-year survival from brain cancer among men varies between 45% and 50% for men and 60% to 70% in women, with excess deaths decreasing with time in each of the Nordic populations. Age-standardised incidence rates of thyroid cancer have been mainly increasing during the 1960s and 1970s, although trends thereafter diverge, with 5-year relative survival increasing 20-30 percentage points over the last 40 years to around 80-90%. Thyroid cancer survival is consistently lower in Denmark, particularly in patients diagnosed aged over 60, while there is less geographic variation in excess deaths three months beyond initial diagnosis. Relative survival from eye cancer increased with time from approximately 60% in 1964-1968 to 80% 1999-2003, while for bone sarcoma, incidence rates remained stable, mortality rates declined, and 5-year survival increased slightly to around 55-65%. Soft tissue sarcoma incidence and survival have been slowly increasing since the 1960s, with little variation in survival (around 65%) for the most recent period. CONCLUSIONS: There have been some notable changes in survival that can be linked to epidemiological and clinical factors in different countries over time. Time-varying proportions of the major histological subtypes might however have affected the survival estimates for a number of the cancer forms reviewed here.

Trends in the survival of patients diagnosed with cancer in female genital organs in the Nordic countries 1964-2003 followed up to the end of 2006.

UNLABELLED: Cancers of the female genital organs constitute more than 12% of all female cancers in the Nordic countries. The group includes cervix uteri, corpus uteri, ovary and other female genital organs including vulva and vagina, and in this study we compare the development in the Nordic countries regarding incidence, mortality and relative survival. MATERIAL AND METHODS: Data were retrieved from the NORDCAN database for the period 1964 to 2003, grouped into eight 5-year periods. The patients were followed up until the end of 2006. Analyses comprised trends in 5-year relative survival, excess mortality and age-specific relative survival. RESULTS: A substantial reduction of cervical cancer incidence followed the introduction of population-based screening in the 1970s and was also accompanied by a modest improvement in survival. Incidence trends in cancer of corpus uteri varied between the countries but the survival increased by around 20 percentage points during the study period in all countries. Ovarian cancer patients have the lowest survival among female genital cancers, but survival increased 10-15 percentage points over the 40 years of observation, while the incidence and mortality were rather stable throughout the observed period. Cancers of the other female genital organs, including vulva and vagina, are rare diagnoses and only small changes in incidence, mortality and survival have been observed over time. CONCLUSION: The declining trends in cervical cancer incidence and mortality, and improving survival of corpus uteri cancer patients, are in contrast with the rather poor prognosis associated with an ovarian cancer diagnosis. Cancer-specific differences between countries in the survival of female patients diagnosed with cancers of the cervix uteri, corpus uteri and other female genital organs are small.

Trends in the survival of patients diagnosed with cancers in the respiratory system in the Nordic countries 1964-2003 followed up to the end of 2006.

BACKGROUND: Previous studies have shown that there have been systematic differences between the Nordic countries in population-based relative survival of patients with respiratory cancer (lung, pleura, larynx, nose and sinuses). MATERIAL AND METHODS: Relative survival of patients with respiratory cancer diagnosed in the Nordic countries in 1964-2003 and followed up to the end of 2006 was studied and contrasted with developments in incidence and mortality. RESULTS: For cancer of the lung, relative survival is lower in Danish patients than in the other countries during the first months of follow-up after diagnosis. For cancer of pleura, the relative survival ratios indicate that there may be problems in the official coding of the causes of death in Denmark, Norway and Sweden. There has been little improvement in survival of patients with cancer of the respiratory organs in the Nordic countries over time. CONCLUSIONS: The slightly lower survival of Danish lung cancer patients may be related to a less favourable stage distribution and to an increased prevalence of causal factors, affecting the mortality due to competing risks of death. A reclassification of official causes of death at the cancer registry may be needed for cancer of the pleura in order to make the corresponding mortality rates comparable between countries.

Trends in the survival of patients diagnosed with cancers of the lip, oral cavity, and pharynx in the Nordic countries 1964-2003 followed up to the end of 2006.

BACKGROUND: This is the first comprehensive population-based study on relative survival of lip, oral cavity and pharyngeal cancer in the Nordic countries. MATERIAL AND METHODS: Relative survival of patients with cancers of the lip, oral cavity, and pharynx diagnosed in the Nordic countries in 1964-2003 and followed up to the end of 2006 was studied and contrasted with trends in incidence and mortality. RESULTS: There are marked differences in incidence between countries and over time. The stability of the relative survival ratios gives support to the hypothesis that the incidence differences are more likely to be real and not materially affected by differences in definitions and coding. Of particular note are the steep rises in pharyngeal cancer incidence in Denmark in both sexes. Survival has only moderately improved over time and has tended to be slightly higher in females than males. CONCLUSIONS: Co-morbidity caused by smoking and high alcohol consumption are likely to be partially responsible for differences between countries. Advances in therapy and standards of care are also likely to have played a role in the increasing survival trends.

Trends in survival of patients diagnosed with male genital cancers in the Nordic countries 1964-2003 followed up until the end of 2006.

BACKGROUND: Prostate, testicular and penile cancer constitute about one-third of the cancer incidence burden among Nordic males, but less than one-fifth of the corresponding mortality. The aim of this study is to describe and interpret trends in relative survival and excess mortality in the five Nordic populations. MATERIAL AND METHODS: Age-standardised incidence and mortality rates, 5-year relative survival, and excess mortality rates for varying follow-up periods are presented, as are age-specific 5-year relative survival by country, sex and 5-year diagnostic period. RESULTS: The vast majority of male genital cancer incident cases and deaths are prostate cancers, with 5-year and 10-year survival trends resembling the diagnostic-led increasing incidence over the past 25 years. Five-year prostate cancer survival is estimated at 53% in Denmark compared to 78% or above in the other Nordic populations for patients diagnosed 1999-2003. Excess mortality has declined over time, with Denmark having a greater excess of deaths compared to the other countries, irrespective of time of diagnosis. Concomitant with the declines in testicular cancer mortality, testicular cancer survival has increased since the 1970s in each Nordic country. Men diagnosed with testicular cancer in recent decades have had, on average, a continually better prognosis with time, with relative 5-year survival for patients diagnosed 1999-2003 ranging from 88% in Finland to 94% in Sweden. For the few patients diagnosed with cancer of the penis and other male genital organs, survival trends have been rather stable over time, with recent 5-year relative survival estimates ranging from 62% in Finland to 80% in Norway. CONCLUSIONS: There are intriguing country-specific and temporal variations in male genital cancer survival in the Nordic countries. Prognosis varies widely by cancer site and relates to both changing diagnostic and clinical practices. The increasing PSA detection and biopsy makes interpretation of the prostate cancer survival trends particularly difficult.

Trends in the survival of patients diagnosed with kidney or urinary bladder cancer in the Nordic countries 1964-2003 followed up to the end of 2006.

BACKGROUND: Previous studies have shown systematic differences between the Nordic Countries in population-based relative survival following a kidney or urinary bladder cancer diagnosis. Comparison of bladder cancer over time and between Nordic registries is complicated by variable coding practices with respect to the inclusion of in situ cases with invasive tumours. MATERIAL AND METHODS: Five-year relative survival of patients with urinary cancer diagnosed in the Nordic countries 1964-2003 and followed up for death through 2006 was studied and contrasted with developments in incidence and mortality. RESULTS: The survival following bladder cancer was higher than for kidney cancer and highest for men. Survival increased over the years in all countries, more for kidney cancer than bladder cancer. For Danish kidney cancer patients, the rate of increase over all the years has been lower than in the other countries, especially among women, resulting in a survival in Denmark some 10-20% points lower than elsewhere in 1999-2003. Danish bladder cancer patient survival was in the last period 4% points lower among men and 10% points lower among women than in the other Nordic countries. The differences were mainly found in the first year following diagnosis, where a higher excess mortality in Denmark was observed. Survival decreased with higher age at diagnosis. CONCLUSION: The increasing 5-year relative survival in all the Nordic countries for both kidney and bladder cancer are promising, but for kidney cancer a higher percentage detected coincidentally during an imaging investigation for other diseases could play a role. Denmark had the lowest survival, despite their known practice of including benign conditions with invasive bladder cancers. The lower Danish survival after kidney and bladder cancer in the first year after diagnosis could be due to later diagnosis on average, a higher co-morbidity from smoking-related diseases, and perhaps, less adequate cancer treatment and management in Denmark.

Waterpipe use predicts progression to regular cigarette smoking among Danish youth.

Waterpipe smoking among Danish, Swedish, and German youth is increasing dramatically, indicating the emergence of a new health threat. This study assessed the association between waterpipe smoking and progression to regular cigarette smoking among Danish continuation school students during 2004-2005. All participants (N = 762) had smoked cigarettes on a nonregular basis at baseline. Among boys, waterpipe smoking frequency was predictive of being a regular cigarette smoker at follow-up eight months later. Further research should examine waterpipe smoking as a potential predictor of cigarette smoking. The study's limitations are noted.

Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial.

BACKGROUND: New glucose-lowering medications need to be investigated in east Asian populations, as the clinical characteristics of type 2 diabetes differ between western and east Asian patients. The PIONEER 10 study aimed to evaluate the safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes. METHODS: PIONEER 10 was an open-label, randomised, active-controlled, phase 3a trial done at 36 sites (clinics and university hospitals) in Japan. Patients aged 20 years and older with uncontrolled type 2 diabetes were randomly assigned (2:2:2:1) to receive once-daily oral semaglutide 3 mg, 7 mg, or 14 mg, or once-weekly subcutaneous dulaglutide 0·75 mg for 52 weeks, as an add-on to their background medication. The primary endpoint was the number of treatment-emergent adverse events over 57 weeks. Supportive secondary endpoints (not controlled for multiplicity) included mean change from baseline in HbA1c and bodyweight at 52 weeks. This trial is registered with ClinicalTrials.gov, NCT03015220. FINDINGS: Between Jan 10, and May 30, 2017, 492 patients were screened and 458 were randomly assigned to oral semaglutide 3 mg (n=131), 7 mg (n=132), or 14 mg (n=130), or dulaglutide 0·75 mg (n=65). 448 (98%) patients completed the trial. Adverse events occurred in 101 (77%) of 131 patients with oral semaglutide 3 mg, 106 (80%) of 132 with oral semaglutide 7 mg, 111 (85%) of 130 with oral semaglutide 14 mg, and 53 (82%) of 65 with dulaglutide. The most common adverse events were infections and gastrointestinal events. Gastrointestinal adverse events (mostly mild and transient constipation and nausea) occurred in a dose-dependent manner with oral semaglutide. Adverse events led to premature treatment discontinuation in four (3%) of 131 patients receiving oral semaglutide 3 mg, eight (6%) of 132 receiving oral semaglutide 7 mg, eight (6%) of 130 receiving oral semaglutide 14 mg, and two (3%) of 65 receiving dulaglutide. No deaths or severe hypoglycaemic events were reported. Based on the treatment policy estimand (ie, regardless of study drug discontinuation or rescue medication use), estimated mean reductions in HbA1c from baseline (8·3%) to week 52 were -0·9 percentage points (SE 0·1) with oral semaglutide 3 mg, -1·4 percentage points (0·1) with oral semaglutide 7 mg, -1·7 percentage points (0·1) with oral semaglutide 14 mg, and -1·4 percentage points (0·1) with dulaglutide (estimated treatment difference -0·3% [95% CI -0·6 to -0·1] for oral semaglutide 14 mg vs dulaglutide; p=0·0170). Estimated mean changes in bodyweight from baseline (72·1 kg) to week 52 were 0·0 kg (SE 0·3) with oral semaglutide 3 mg, -0·9 kg (0·3) with oral semaglutide 7 mg, -1·6 kg (0·3) with oral semaglutide 14 mg, and 1·0 kg (0·4) with dulaglutide (estimated treatment difference -2·6 kg [95% CI -3·5 to -1·6] for oral semaglutide 14 mg vs dulaglutide; p<0·0001). INTERPRETATION: Oral semaglutide was well tolerated in Japanese patients with type 2 diabetes. Once-daily oral semaglutide significantly reduced HbA1c (14 mg dose) and bodyweight (7 mg and 14 mg doses) versus weekly subcutaneous dulaglutide 0·75 mg by week 52. FUNDING: Novo Nordisk.

Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study.

OBJECTIVES: Fluconazole is widely used for the treatment of candidiasis. Although the drug is also prescribed to pregnant women, data on the safety of use of fluconazole during pregnancy are limited. We examined the association between the maternal use of fluconazole during pregnancy and the risk of congenital malformations. PATIENTS AND METHODS: In this population-based cohort study in Northern Denmark, we included 1079 women who had a live birth or a stillbirth after the 20th week of gestation and who redeemed at least one prescription for fluconazole during the first trimester. The reference cohort comprised 170 453 pregnant women who redeemed no fluconazole prescription during pregnancy. The women were identified through the Danish Medical Birth Registry. Data on drug use, birth outcome and covariates were extracted from population-based healthcare databases. We used logistic regression to estimate the prevalence odds ratio (POR) for congenital malformations after fluconazole exposure, while adjusting for maternal smoking, parity, maternal age and concurrent prescriptions for antiepileptics or antidiabetics. RESULTS: Among 1079 women who filled a fluconazole prescription during the first trimester, 797 (74%) received a total of 150 mg of fluconazole, 235 (22%) received 300 mg of fluconazole, 24 (2%) received 350 mg of fluconazole and 23 (2%) received 600 mg of fluconazole. These women gave birth to 44 (4.1%) children with congenital malformations. The 170 453 women without fluconazole prescriptions gave birth to 6152 (3.6%) children with congenital malformations. For congenital malformations overall, the adjusted POR associated with the first-trimester fluconazole use was 1.0 (95% confidence interval: 0.8-1.4). CONCLUSIONS: We found no overall increased risk of congenital malformations after exposure to short-course treatment with fluconazole in early pregnancy.

Liver cirrhosis, other liver diseases, and risk of hospitalisation for intracerebral haemorrhage: a Danish population-based case-control study.

BACKGROUND: Liver diseases are suspected risk factors for intracerebral haemorrhage (ICH). We conducted a population-based case-control study to examine risk of ICH among hospitalised patients with liver cirrhosis and other liver diseases. METHODS: We used data from the hospital discharge registries (1991-2003) and the Civil Registration System in Denmark, to identify 3,522 cases of first-time hospitalisation for ICH and 35,173 sex- and age-matched population controls. Among cases and controls we identified patients with a discharge diagnosis of liver cirrhosis or other liver diseases before the date of ICH. We computed odds ratios for ICH by conditional logistic regressions, adjusting for a number of confounding factors. RESULTS: There was an increased risk of ICH for patients with alcoholic liver cirrhosis (adjusted OR = 4.8, 95% CI: 2.7-8.3), non-alcoholic liver cirrhosis (adjusted OR = 7.7, 95% CI: 2.0-28.9) and non-cirrhotic alcoholic liver disease (adjusted OR = 5.4, 95%CI:3.1-9.5) but not for patients with non-cirrhotic non-alcoholic liver diseases (adjusted OR = 0.9, 95%CI:0.5-1.6). The highest risk was found among women with liver cirrhosis (OR = 8.9, 95%CI:2.9-26.7) and for patients younger than 70 years (OR = 6.1, 95%CI:3.4-10.9). There were no sex- or age-related differences in the association between other liver diseases (alcoholic or non-alcoholic) and hospitalisation with ICH. CONCLUSION: Patients with liver cirrhosis and non-cirrhotic alcoholic liver disease have a clearly increased risk for ICH.

Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study.

BACKGROUND: Smoking and obesity are associated with adverse pregnancy outcomes. The aim of the present study was to examine the association between smoking, obesity (BMI>30), and risk for venous thromboembolism (VTE) during pregnancy and the puerperium. MATERIALS AND METHODS: In a population-based case-control study nested within a Danish cohort of 71,729 women, we identified 129 cases with VTE in pregnancy or the puerperium, and 258 pregnant non-VTE controls. We obtained data from medical records regarding current smoking status, BMI, and other covariates, and computed the odds ratios (OR) for VTE as a measure of relative risk. RESULTS: Smoking and obesity were associated with increased risk of VTE during pregnancy and the puerperium (adjusted OR 2.7 (95% CI: 1.5, 4.9) and 5.3 (95% CI: 2.1, 13.5), respectively). Obesity appeared to be associated with a higher risk of pulmonary embolism (adjusted OR: 14.9 (95% CI: 3.0, 74.8) than of deep venous thrombosis (adjusted OR: 4.4, 95% CI: 1.6, 11.9). CONCLUSION: Smoking and obesity are risk factors for VTE in pregnancy and the puerperium.