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Aims/hypothesis Mortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality. Methods We assembled aggregate data on all-cause mortality during the period 2000–2016 in people with type 1 diabetes aged 0–79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes. Results All six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from −2.1% (95% CI −2.8%, −1.3%) to −5.8% (95% CI −6.5%, −5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40–70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources. Conclusions/interpretation All-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent. Graphical abstract

BackgroundContinued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies.MethodsThe EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014–2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined.FindingsAmong 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions.InterpretationResults from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors. Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies. Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014–2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined. Findings: Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions. Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.

Aims: To estimate the incidence rates of genital warts (GWs) in women and men with type 1 diabetes compared to persons without diabetes. Methods: In this nationwide registry-based cohort study, we included the entire population aged 15 to 49 years living in Denmark between 1996 and 2016. From national registries, we retrieved individual level information on diabetes status, diagnoses and treatment of GWs, and potential confounding variables. We used Poisson regression to model sex- and age-specific incidence rates of GWs in persons with type 1 diabetes and persons without diabetes. Based on the models, we computed sex-specific incidence rate ratios (IRRs) of GWs in persons with type 1 diabetes compared to persons without diabetes, overall and according to age. Results: The analysis included 3,514,824 persons without type 2 diabetes and no GW diagnoses before baseline. The incidence rate of GWs in persons with type 1 diabetes was higher than in those without diabetes, both among women (IRR = 1.59; 95% CI, 1.42–1.78) and men (IRR = 1.36; 95% CI, 1.25–1.48). The pattern of increased incidence rates of GWs in persons with type 1 diabetes was seen at all ages. Conclusions: Persons with type 1 diabetes have higher incidence rates of GWs than persons without diabetes. This supports the importance of HPV vaccination of young girls and boys with type 1 diabetes.

Background: Complications can be present at type 2 diabetes (T2D) diagnosis or develop later. We describe trends in burden of ischaemic heart disease (IHD) in T2D. Methods: T2D cases in Denmark 1996-2020 in a national diabetes register were used. Events of IHD 1994-2020 were from the National Patient Register. Prevalence of IHD at time of T2D was described by a binomial model. New IHD and death during follow-up were analysed by rate models and used to estimate the time in the states (no IHD / IHD at T2D / IHD after T2D) . Results: 410,4 persons with T2D 1996-2020 were included; 61,378 with pre-existing IHD. Prevalence of IHD at T2D diagnosis was increasing 1.7%/year. Incidence rates of IHD after diagnosis was decreasing 5.7%/year. Mortality among T2D persons without IHD decreased 5.7%/year; for those with IHD it decreased 3.5%/year. During the first years, expected lifetime was 8.1 and 8.8 years for men diagnosed at age 65 in 1998 and 2018, respectively. Time without IHD was 6.2 and 6.9 years, with new IHD 0.9 and 0.5 years and with preexisting IHD 1.0 and 1.5 years in 1998 and 2018. We saw an increase in expected lifetime, partly as increase in lifetime with preexisting IHD. Similar patterns were seen for women and for persons diagnosed in other ages. Conclusions: We saw an increase in expected lifetime, as well as decreasing mortality rates regardless of IHD status. Prevalence of IHD at the time of diagnosis was increasing, possibly due to more detailed diagnoses of IHD; in our data only IHD complications after 1994 are included which may be a partial explanation of the increase in prevalent IHD at the date of T2D diagnosis. In general the IHD burden in T2D in Denmark is decreasing. Disclosure B.Carstensen: Stock/Shareholder; Novo Nordisk A/S. K.K.Clemmensen: Employee; Novo Nordisk A/S, Research Support; AstraZeneca, Novo Nordisk Foundation, Stock/Shareholder; Lundbeck, Novo Nordisk A/S. H.Amadid: Stock/Shareholder; Novo Nordisk.

Summary Background Diabetes prevalence is increasing in most places in the world, but prevalence is affected by both risk of developing diabetes and survival of those with diabetes. Diabetes incidence is a better metric to understand the trends in population risk of diabetes. Using a multicountry analysis, we aimed to ascertain whether the incidence of clinically diagnosed diabetes has changed over time. Methods In this multicountry data analysis, we assembled aggregated data describing trends in diagnosed total or type 2 diabetes incidence from 24 population-based data sources in 21 countries or jurisdictions. Data were from administrative sources, health insurance records, registries, and a health survey. We modelled incidence rates with Poisson regression, using age and calendar time (1995–2018) as variables, describing the effects with restricted cubic splines with six knots for age and calendar time. Findings Our data included about 22 million diabetes diagnoses from 5 billion person-years of follow-up. Data were from 19 high-income and two middle-income countries or jurisdictions. 23 data sources had data from 2010 onwards, among which 19 had a downward or stable trend, with an annual estimated change in incidence ranging from −1·1% to −10·8%. Among the four data sources with an increasing trend from 2010 onwards, the annual estimated change ranged from 0·9% to 5·6%. The findings were robust to sensitivity analyses excluding data sources in which the data quality was lower and were consistent in analyses stratified by different diabetes definitions. Interpretation The incidence of diagnosed diabetes is stabilising or declining in many high-income countries. The reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources. Funding US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

OBJECTIVE Experiencing adversities in childhood may increase the risk of type 1 diabetes through hyperactivation of the stress response system, but the empirical evidence is conflicting. We aim to describe the age-specific incidence of type 1 diabetes for males and females separately in five predefined groups covering the most common trajectories of adversity among Danish children. RESEARCH DESIGN AND METHODS We included all 1,081,993 children without parental type 1 diabetes born in Denmark from 1980 to 1998. We used register data to estimate age-specific incidence rates of type 1 diabetes in five trajectory groups of adversity characterized by 1) low adversity, 2) early life material deprivation, 3) persistent material deprivation, 4) loss or threat of loss in the family, and 5) cumulative high adversity. All analyses were stratified by sex. RESULTS In total, 5,619 people developed type 1 diabetes before 2016. We found only minor differences when comparing the incidence rates of type 1 diabetes between the trajectory groups. The only clear exceptions were in the high versus low adversity group, in which males had a higher incidence of type 1 diabetes in childhood ( CONCLUSIONS Childhood adversities were generally not associated with age-specific incidence of type 1 diabetes except among those exposed to a very high and increasing annual rate of childhood adversities. Differences between highly exposed males and females seem to depend on age at onset of type 1 diabetes.

Background People with type 1 diabetes often live for many years with different combinations of diabetes-related complications. We aimed to quantify how complication duration and total complication burden affect mortality, using data from national registers. Methods This study included 33 396 individuals with type 1 diabetes, registered in the Swedish National Diabetes Register at any time between 2001 and 2012. Each individual was followed and classified according to their time-updated diabetes-related complication status. The main outcomes were all-cause mortality, cardiovascular (CV) mortality and non-CV mortality. Poisson models were used to estimate the rate of these outcomes as a function of the time-updated complication duration. Results Overall, 1748 of the 33 396 individuals died during 198 872 person-years of follow-up. Overall, the time-updated all-cause mortality rate ratio (MRR) was 2.25 [95% confidence interval (CI): 1.99–2.54] for patients with diabetic kidney disease, 0.98 (0.82–1.18) for patients with retinopathy and 4.00 (3.56–4.50) for patients with cardiovascular disease relative to individuals without complications. The excess rate was highest in the first period after a diagnosis of CVD, with an 8-fold higher mortality rate, and stabilized after some 5 years. After diagnosis of diabetic kidney disease, we observed an increase in all-cause mortality with an MRR of around 2 compared with individuals without diabetic kidney disease, which stabilized after few years. Conclusions In this cohort we show that duration of diabetes-related complications is an important determinant of mortality in type 1 diabetes, for example the MRR associated with CVD is highest in the first period after diagnosis of CVD. A stronger focus on time-updated information and thorough consideration of complication duration may improve risk stratification in routine clinical practice.

BackgroundPrevious studies have indicated an association between childhood adversities and type 1 diabetes but have been underpowered and limited by selection. We aim to quantify the effect of accumulation of childhood adversities on type 1 diabetes risk, and to assess whether the effect differs between males and females in a large and unselected population sample.MethodsWe used register-based data covering all children born in Denmark between 1980 and 2015, totalling >2 million children. We specified a multi-state model to quantify the effect of accumulation of childhood adversities on type 1 diabetes risk. The effects of specific childhood adversities on type 1 diabetes were estimated using proportional hazards models.ResultsAccumulation of childhood adversities had a quantitatively small effect on type 1 diabetes risk among females [adjusted hazard ratio (HR) per adversity increase: 1.07; 95% confidence interval (CI): 1.02–1.11], but not among males (adjusted HR per adversity increase: 0.99; 95% CI: 0.97–1.03). Females exposed to extreme numbers (7+) of adversities had two times higher risk of type 1 diabetes compared with unexposed females (adjusted HR: 2.06; 95% CI: 1.10–3.86).ConclusionsIn an unselected total population sample, we generally find no or negligible effects of childhood adversities on type 1 diabetes risk, which may be reassuring to persons with type 1 diabetes who are concerned that personal trauma contributed to their disease. There is a very small group of females exposed to a high degree of adversity who may have a higher risk of type 1 diabetes and this group needs further attention.

Background: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61–0·77; p

BACKGROUND: Diabetes is a major public health issue. Because lifetime risk, life expectancy, and years of life lost are meaningful metrics for clinical decision making, we aimed to estimate these measures for type 2 diabetes in the high-income setting.; METHODS: For this multinational, population-based study, we sourced data from 24 databases for 23 jurisdictions (either whole countries or regions of a country): Australia; Austria; Canada; Denmark; Finland; France; Germany; Hong Kong; Hungary; Israel; Italy; Japan; Latvia; Lithuania; the Netherlands; Norway; Scotland; Singapore; South Korea; Spain; Taiwan; the UK; and the USA. Our main outcomes were lifetime risk of type 2 diabetes, life expectancy in people with and without type 2 diabetes, and years of life lost to type 2 diabetes. We modelled the incidence and mortality of type 2 diabetes in people with and without type 2 diabetes in sex-stratified, age-adjusted, and calendar year-adjusted Poisson models for each jurisdiction. Using incidence and mortality, we constructed life tables for people of both sexes aged 20-100 years for each jurisdiction and at two timepoints 5 years apart in the period 2005-19 where possible. Life expectancy from a given age was computed as the area under the survival curves and lifetime lost was calculated as the difference between the expected lifetime of people with versus without type 2 diabetes at a given age. Lifetime risk was calculated as the proportion of each cohort who developed type 2 diabetes between the ages of 20 years and 100 years. We estimated 95% CIs using parametric bootstrapping.; FINDINGS: Across all study cohorts from the 23 jurisdictions (total person-years 1577234194), there were 5119585 incident cases of type 2 diabetes, 4007064 deaths in those with type 2 diabetes, and 11854043 deaths in those without type 2 diabetes. The lifetime risk of type 2 diabetes ranged from 16·3% (95% CI 15·6-17·0) for Scottish women to 59·6% (58·5-60·8) for Singaporean men. Lifetime risk declined with time in 11 of the 15 jurisdictions for which two timepoints were studied. Among people with type 2 diabetes, the highest life expectancies were found for both sexes in Japan in 2017-18, where life expectancy at age 20 years was 59·2 years (95% CI 59·2-59·3) for men and 64·1 years (64·0-64·2) for women. The lowest life expectancy at age 20 years with type 2 diabetes was observed in 2013-14 in Lithuania (43·7 years [42·7-44·6]) for men and in 2010-11 in Latvia (54·2 years [53·4-54·9]) for women. Life expectancy in people with type 2 diabetes increased with time for both sexes in all jurisdictions, except for Spain and Scotland. The life expectancy gap between those with and without type 2 diabetes declined substantially in Latvia from 2010-11 to 2015-16 and in the USA from 2009-10 to 2014-15. Years of life lost to type 2 diabetes ranged from 2·5 years (Latvia; 2015-16) to 12·9 years (Israel Clalit Health Services; 2015-16) for 20-year-old men and from 3·1 years (Finland; 2011-12) to 11·2 years (Israel Clalit Health Services; 2010-11 and 2015-16) for 20-year-old women. With time, the expected number of years of life lost to type 2 diabetes decreased in some jurisdictions and increased in others. The greatest decrease in years of life lost to type 2 diabetes occurred in the USA between 2009-10 and 2014-15 for 20-year-old men (a decrease of 2·7 years).; INTERPRETATION: Despite declining lifetime risk and improvements in life expectancy for those with type 2 diabetes in many high-income jurisdictions, the burden of type 2 diabetes remains substantial. Public health strategies might benefit from tailored approaches to continue to improve health outcomes for people with diabetes.; FUNDING: US Centers for Disease Control and Prevention and Diabetes Australia. Copyright © 2022 Elsevier Ltd. All rights reserved.

Context Individuals with severe mental illness (SMI) are at increased risk of developing type 2 diabetes. Objective This work explores whether individuals with diabetes and SMI are also at increased risk of diabetes complications and the potential age-specific differences in development of these. Methods Using nationwide registry data, we followed the entire Danish population with type 2 diabetes from January 1, 1996 to December 31, 2018. Exposure was SMI (schizophrenia, bipolar, or depression disorders). Outcome was diabetes complications (nephropathy, retinopathy, lower limp amputations, and cardiovascular disease). We applied Poisson regression models to estimate overall incidence rate ratios (IRRs) and age-specific incidence rates (IRs) and IRRs of the first event of each complication in individuals with SMI compared to individuals without SMI. The models were adjusted for sex, age, diabetes duration, calendar year, education, and migration status. Results We followed 371 625 individuals with type 2 diabetes, of whom 30 102 had coexisting diagnosed SMI. Individuals with SMI had a higher IR of nephropathy (IRR: 1.15; 95% CI, 1.12-1.18), amputations (IRR: 1.15; 95% CI, 1.04-1.28), and cardiovascular disease (men: IRR: 1.10; 95% CI, 1.05-1.15, women: IRR: 1.18; 95% CI, 1.13-1.22) but a lower IR of retinopathy (IRR: 0.75; 95% CI, 0.70-0.81) when compared to individuals without SMI, after adjustment for confounders. For all complications except amputations, the difference in IR was highest in the younger age groups. Conclusion Individuals with type 2 diabetes and SMI had a higher risk and an earlier onset of several diabetes complications diagnoses, emphasizing focusing on improving diabetes management in younger age groups with SMI.

Mortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality.We assembled aggregate data on all-cause mortality during the period 2000-2016 in people with type 1 diabetes aged 0-79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes.All six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from -2.1% (95% CI -2.8%, -1.3%) to -5.8% (95% CI -6.5%, -5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40-70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources.All-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent.

Aim: To assess lipid-lowering drug (LLD) use patterns during 1996-2017 and examine lipid levels in relation to the use of LLDs and prevalent atherosclerotic cardiovascular disease (ASCVD). Methods: Using a nationwide diabetes register, 404 389 individuals with type 2 diabetes living in Denmark during 1996-2017 were identified. Individuals were followed from 1 January 1996 or date of type 2 diabetes diagnosis until date of emigration, death or 1 January 2017. Redemptions of prescribed LLDs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels were sourced from the National Laboratory Database since 2010. LLD coverage was calculated at any given time based on the redeemed amount and dose. Trends in lipid levels were estimated using an additive mixed-effect model. Low-density lipoprotein cholesterol (LDL-C) goal attainment was assessed based on recommended targets by the 2011, 2016 and 2019 guidelines for management of dyslipidaemias. Results: LLD use has decreased since 2012 and only 55% of those with type 2 diabetes were LLD users in 2017. A decline in levels of total cholesterol and LDL-C, and an increase in triglycerides, was observed during 2010-2017. Annual mean levels of LDL-C were lower among LLD users compared with non-users (in 2017: 1.84 vs. 2.57 mmol/L). A greater fraction of LLD users achieved the LDL-C goal of less than 1.8 mmol/L compared with non-users (in 2017: 51.7% and 19%, respectively). Among LLD users with prevalent ASCVD, 26.9% and 55% had, as recommended by current 2019 European guidelines, an LDL-C level of less than 1.4 mmol/L and less than 1.8 mmol/L, respectively, in 2017. Conclusions: LLD use and LDL-C levels are far from optimal in the Danish type 2 diabetes population and improvement in LLD use could reduce ASCVD events.

Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes.In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR).In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources.All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes.US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Background: Diabetes may increase risk of human papillomavirus (HPV)-related precancer and cancer. We estimated incidence of penile and anal high-grade intraepithelial neoplasia (hgPeIN, hgAIN) and squamous cell carcinoma (SCC) in men with diabetes compared with the entire Danish male population without diabetes. Methods: In this registry-based cohort study, we included all men born 1916-2001 and residing in Denmark (n = 2,528,756). From nationwide registries, we retrieved individual-level information on diabetes, educational level, and diagnoses of hgPeIN, hgAIN, penile SCC, and anal SCC. We used Poisson regression models to estimate incidence of hgPeIN, hgAIN, penile SCC, and anal SCC as a function of diabetes status, attained age, calendar period, and education. We estimated incidence rate ratios (IRRs) of each outcome in men with diabetes compared with nondiabetic men, both for diabetes overall and separately for type 1 (T1D) and type 2 diabetes (T2D). Results: Men with diabetes had increased incidence rate of penile SCC compared with nondiabetic men (IRR = 1.5, 95% CI = 1.2, 1.9). We saw similar trends for anal SCC, hgPeIN, and hgAIN. The combined incidence rate of penile and anal SCC was increased in men with T2D (IRR = 1.5, 95% CI = 1.3, 1.8), but not with T1D (IRR = 0.53, 95% CI = 0.20, 1.4) compared with men without diabetes. Conclusion: The incidence of penile and anal high-grade intraepithelial neoplasia and SCC in men with diabetes was increased compared with men without diabetes. For penile and anal SCCs, this was primarily due to an increased risk in men with T2D.

Discontinuation of diabetes medication in the last years of life has been suggested to improve quality of life while deemed safe to implement. However, the extent, patterns, and secular changes in discontinuation of glucose-lowering medication in older people with type 2 diabetes have been scarcely described. We therefore aimed to describe the trends in the use of glucose-lowering medication during the last 10 years of life of older people and explore how key clinical and socioeconomic covariates are associated with these patterns.In this register-based cohort study, all individuals with type 2 diabetes who died aged 80 years or older between Jan 1, 2006, and Dec 31, 2018, were identified through the Danish Diabetes Register and linked to the Danish National Prescription Registry. We followed the population backwards in time from death to date of last medication intake. To estimate the cumulative proportion of people on glucose-lowering medication, a Poisson regression model for the rate of medication as a function of time before death (0 to 10 years before death) and calendar year of death (2006-18) was fitted. Both single-substance and combination glucose-lowering medications were included and categorised as insulins, sulfonylureas, metformin, DPP-4 inhibitors, GLP-1 analogues, SGLT2 inhibitors, acarbose, and thiazolidinediones. Insulin was further subdivided into four groups: fast-acting, intermediate-acting, long-acting, and mixed insulin. To identify which covariates were associated with discontinuation, estimates were adjusted for sex, age at death, diabetes duration at time of death, the total number of diabetes complications at time of death (from no complications to four or more), level of education, immigrant status, and income quartile.52 523 individuals (28 746 [54·7%] females and 23 777 [45·3%] males) were identified, with a mean age at type 2 diabetes diagnosis of 77 years (SD 8), median age at death of 86 years (IQR 83-90), and median diabetes duration at death of 9 years (IQR 5-14). We found a considerable discontinuation of glucose-lowering medication during the last 10 years of life, with the proportion of people on glucose-lowering medication starting at between 89% (95% CI 87-91) in 2006 and 87% (86-88) in 2018 at 10 years before death and decreasing to between 52% (50-54) in 2006 and 38% (37-39) in 2018 at the time of death. Specifically, we found that the proportion of people on sulfonylureas, at any time before death, decreased substantially from 2006 to 2018, whereas the proportion on metformin and DPP-4 inhibitors increased with calendar year of death. Changes were less pronounced for the remaining medications. The overall discontinuation patterns changed with increasing calendar year of death, such that discontinuation rates increased and occurred earlier (further away from time of death) with increasing calendar year. Discontinuations were generally more pronounced during the last year of life. Proportions of people on medication and patterns of discontinuation, as well as the association with covariates, varied with medication class. Covariates most frequently associated with changes in discontinuation rates were sex, age at death, type 2 diabetes duration at death, and number of complications. For example, females were less likely to receive metformin than males at all years before death (rate ratio 0·91 (95% CI 0·89-0·94, p0·0001), and there was a negative association between the proportion of individuals on metformin and increasing age at death (rate ratio per year increase 0·96 [0·96-0·96], p0·0001) and type 2 diabetes duration (0·95 per year increase [0·94-0·95], p0·0001).Our results suggest that increased focus on and implementation of discontinuation of glucose-lowering medication in recent years might have had an effect on discontinuation patterns, particularly during the last year of life.None.

Some studies have suggested a declining mortality in type 1 diabetes, but it is unclear if the pattern of mortality trends differs by country and age group, and how mortality trends in type 1 diabetes relate to trends in the general population mortality. We assembled aggregated data on all-cause mortality in people with type 1 diabetes by 5-year age group and sex between 2000 and 2016 from an international diabetes consortium database, GLOBODIAB. Data were from administrative sources, health insurance records and registries. We used joinpoint regression analysis to examine trends in annual mortality rates (standardized to the 2010 European Union population) and mortality rate ratios (MRRs) (relative to the mortality in people without diabetes) in all age groups, and stratified by age ( In conclusion, all-cause mortality in type 1 diabetes has declined in recent years in the majority of data sources, but remains considerably higher than in the nondiabetic population. These data highlight that there is still scope to improve mortality in type 1 diabetes and reduce inequalities within and between populations. Disclosure P. Lopez-doriga ruiz: None. G. A. Nichols: Research Support; Self; Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, National Institute of Diabetes and Digestive and Kidney Diseases. S. Pildava: None. S. H. Read: Employee; Self; Certara. S. Wild: Advisory Panel; Self; Gilead Sciences, Inc., Other Relationship; Self; Novo Nordisk. J. E. Shaw: Advisory Panel; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Pfizer Inc., Research Support; Self; AstraZeneca, Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk. D. J. Magliano: None. L. Chen: None. J. I. Morton: None. A. Salim: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk. E. W. Gregg: None. M. E. Pavkov: None. M. Mata-cases: Consultant; Self; Mundipharma International, Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD Corporation, Novo Nordisk. D. Mauricio: None. Funding Centers for Disease Control and Prevention

In the elderly population with type 2 diabetes (T2D), decisions about discontinuation of medication is important, as it may lead to improved outcomes and reduced polypharmacy-associated adverse events. However, the extent, patterns and secular changes of discontinuation of cardioprotective medication during the last years of life have been scarcely described. All individuals with T2D that died at age ≥ 80, between 2006-2018 were identified through the Danish Diabetes Register and linked to the Register of Medicinal Products Statistics. The population was followed backward in time, from death to date of last intake of cardioprotective medication. To estimate the cumulative proportion on different medication classes, we fitted a crude Poisson regression model for the rate of medication with time before death. A total of 52,523 persons (55% female) were identified, with a mean (SD) age at T2D diagnosis of 77 (8) years, a median (Q1-Q3) age at death of 86 (83-90) years and a median (Q1-Q3) diabetes duration at death of 9 (5-14) years. From year of death in 2006 to 2018, we found an increased utilization of antihypertensive and lipid-lowering medication, during the last 10 years of life, while the opposite was true for aspirin (ASA) (Figure 1). We also found a simultaneous increase in discontinuation rates during the last years of life, which was particularly pronounced during the last year of life. Disclosure V. Kosjerina: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk. M. E. Jorgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. B. Brock: None. H. Christensen: None. J. Rungby: None. G. S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

Background: Severe mental illness (SMI) is linked with a higher incidence of type 2 diabetes (T2D); however, it is unclear whether persons with SMI and T2D have a higher incidence of diabetes complications compared to persons with T2D only. We calculated incidence rate ratios (IRR) and incidence rates (IR) of micro- and macrovascular diabetes complications among persons with T2D and SMI compared to those with T2D only. Methods: We used Danish nationwide registers to follow all persons with T2D from 1996 to 2018. IRR and age-specific IR of first event of each diabetes complication was estimated using Poisson regression models with risk time as offset comparing persons with T2D with and without SMI, while adjusting for sex, age, diabetes duration, calendar year, substance abuse and Charlson’s Comorbidity Index. Results: A total of 371,625 persons with T2D were on average followed for 6.9 - 7.6 year depending on the complication outcome. Persons with T2D and SMI (n=29,249) were younger at T2D diagnosis than persons with T2D only (mean [SD], 59 [15] vs. 63 [14] year). In total, 73,598 (27%) developed cardiovascular disease (CVD), 25,846 (7%) developed retinopathy, 20,191 (5%) developed nephropathy, and 6,796 (2%) underwent an amputation during follow-up. Persons with T2D and SMI had an increased risk of CVD (IRR: 1.14 (95% CI: 1.11-1.18)) and nephropathy (IRR: 1.11 (95% CI: 1.03-1.16)), and a decreased risk of retinopathy (IRR: 0.83 (95% CI: 0.78-0.86)) compared to persons with T2D only when adjusting for confounders. The risk for amputations were similar in persons with T2D with and without SMI (IRR: 1.00 (95% CI: 0.90-1.12)). The increased risk of CVD and nephropathy in persons with SMI were persistent in all ages except for the ages 80-95 year. Conclusion: Persons with T2D and SMI have a slightly higher risk of CVD and nephropathy and a lower risk of retinopathy compared to persons with T2D only. Disclosure S. H. Scheuer: None. V. Kosjerina: None. N. Lindekilde: None. F. Pouwer: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk. M. E. Jørgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. M. E. Benros: None. G. S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio [OR] 6.9; 95% confidence interval [CI]: 5.6–8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057-–0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function.

We evaluated the associations of age and duration of type 2 diabetes with major diabetes-related complications.We included 1.1 million people with type 2 diabetes from the Australian diabetes registry, followed from 2010 to 2019. We estimated the incidence of hospitalization or death from myocardial infarction (MI), stroke, and heart failure (HF), and hospitalisation for lower extremity amputation (LEA); end-stage kidney disease (ESKD; kidney replacement therapy or death from ESKD); and all-cause mortality. Poisson regression was used to model incidence by attained age, age at diabetes diagnosis, and duration of diabetes.Risk for complications increased exponentially with diabetes duration. Effects of attained age differed for each complication: age was a strong risk factor for MI, stroke, HF, and mortality, while diabetes duration, not age, was the predominant determinant of LEA and ESKD. At a given age, a 10-year longer diabetes duration was associated with a 1.1-1.5-fold increased risk of stroke and mortality, a 1.5-2.0-fold increased risk of MI and HF, and a 2-4-fold increased risk of LEA and ESKD.Duration of diabetes is a stronger risk factor for ESKD and LEA than it is for cardiovascular disease or mortality.

In this register-based cohort study, we estimated the incidence of human papillomavirus (HPV)-related anogenital precancer and cancer in women with diabetes compared with women without diabetes. We followed all women living in Denmark born 1916 to 2001 (n = 2 508 321) for individual-level information on diabetes (Type 1 or 2 [T1D or T2D]), diagnoses of cervical, vaginal, vulvar and anal intraepithelial neoplasia Grade 2 or 3 (IN2/3) and cancer and other covariates from nationwide registries. We used Poisson regression to model the incidence rates of anogenital IN2/3 and cancer as a function of diabetes status, age, HPV vaccination, education, calendar year, and cervical cancer screening status. Incidence rate ratios (IRRs) were estimated for diabetes overall, and separately for T1D and T2D, compared with women without diabetes. Women with diabetes had higher rates of vulvar IN2/3 (IRR = 1.63; 95% confidence interval [CI]: 1.41-1.88), vulvar cancer (IRR = 1.61; 95% CI: 1.36-1.91) and vaginal cancer (IRR = 1.79; 95% CI: 1.27-1.91) than women without diabetes. Similar patterns were observed for anal IN2/3, anal cancer and cervical cancer, although not statistically significant. In contrast, women with diabetes had lower rates of cervical IN2/3 (IRR = 0.74; 95% CI: 0.69-0.79) than women without diabetes. Patterns were generally similar in women with T1D and T2D, although cancer rates were higher in women with T2D. In conclusion, the incidence of most anogenital precancers and cancers were increased in women with diabetes. However, women with diabetes had lower incidence of cervical precancer. Our findings could be explained by biological mechanisms and/or behavioral factors, such as smoking and less frequent cervical screening participation.

This chapter examines prevalence data, using a dataset which contains the number of diabetes patients and the total number of persons in Denmark as of January 1, 2010, classified by age and sex. Prevalence of a disease condition in a population is merely the proportion of affected people. The chapter uses prevalence to illustrate core modelling concepts: the model itself, the likelihood, the maximum likelihood estimation principle, and the properties of the results, all of which underlies most modern epidemiological methods. It also explains the concept of a statistical model leading to the distinction between empirical and theoretical prevalences. The chapter then focuses on the task of comparing different models for the same data, models that describe data in various degrees of detail.

The code shown in each chapter is available at the website http://bendixcarstensen.com/EwR (this URL is case-sensitive). You will benefit from running it on your own computer and use R to look further into the various data structures you create on the way (‘objects’ as we call them)....

This chapter discusses how the best way to learn R is to use it. One should start by using it as a simple calculator, and keep on exploring what one gets back by inspecting the size, shape, and content of what one creates. R is available from CRAN, the Comprehensive R Archive Network. A nice interface to R is RStudio, which is a commercial product, but RStudio has a free open source license that allows one to have a very good and handy interface to R for free, including the possibility of writing reports using Rmarkdown, Sweave, or knitr. The chapter then looks at the two main graphics systems used in R: base graphics, which is an integral part of any R distribution, and ggplot2 (gg referring to grammar of graphics). Data from large epidemiological studies are often summarized in the form of frequency data, which record the frequency of all possible combinations of values of the variables in the study.

This chapter addresses Case-control and case-cohort studies. In a Case-control study, one samples persons based on their disease outcome, so the fraction of diseased persons in a Case-control study is usually known (at least approximately) before data collection. In a cohort (follow-up) study, the relationship between some exposure and disease incidence is investigated by following the entire cohort and measuring the rate of occurrence of new cases in the different exposure groups. The follow-up records all persons who develop the disease during the study period. Implicit in this is that the relevant exposure information is available at all times for all persons under follow-up. The chapter then looks at the statistical model for the odds ratio, before differentiating between odds ratio and rate ratio. It also considers confounding and stratified sampling; individually matched studies; and nested Case-control studies.

This chapter assesses the analysis and representation of follow-up data. follow-up refers to the process of monitoring persons over time for occurrence of a (set of) prespecified event(s). Practical data collection is often via look-up in registers or databases. The basic requirements for recordings in a follow-up study include date of entry to the study, date of exit from the study, and the status of the person at the exit date. The chapter then explains the likelihood from a follow-up study and why one can analyse rates using Poisson regression. The likelihood contribution from a single person's follow-up can be subdivided in contributions from subintervals of the follow-up. The chapter details the task of splitting the follow-up time along a time-scale. Finally, it considers time-dependent variables.

This chapter provides an overview of parametrizing quantitative covariate effects, that is, describing how variables (covariates) influence the outcome variable, be that disease odds, rates, or some quantitative measurement. It begins by differentiating between predictions and contrasts. When reporting rate ratios between two groups or the odds ratio of a disease associated with a certain difference in exposure, one is using contrasts of the outcome variable between different values of a covariate to describe the effect. Thus, one uses ratios or differences. But when reporting the mortality rate in, say, 60-year-old males, one is making a prediction of the outcome. This requires a set of values for all covariates in a model. When describing the effects of covariates by a model, one normally uses a linear predictor. The chapter then discusses the prediction of a single rate; categorical variables; the task of modelling the effect of quantitative variables; quantitative predictors; and quantitative interactions.

This chapter provides a brief introduction to some of the most common measures of disease occurrence used in epidemiology, both the empirical and theoretical versions of the measures. It begins with the prevalence of a disease in a population, which is the fraction of the population that has the disease at a given date. The chapter then considers mortality rate, incidence rate, standardized mortality ratio (SMR), and survival. Mortality is typically reported as a number of people that have died in a population of a certain size. Incidence rates are defined exactly as mortality rates, where one just counts incident cases, that is, newly diagnosed cases of a particular disease. Meanwhile, the SMR is a measure of the mortality in a group of persons as compared to the general population. Finally, the survival after diagnosis of a disease is defined as the fraction of diagnosed individuals alive at a given time after diagnosis.

This book is a practical guide designed for students and researchers with an existing knowledge of R who wish to learn how to apply it in an epidemiological context and exploit its versatility. It also serves as a broader introduction to the quantitative aspects of modern practical epidemiology. The standard tools used in epidemiology are described and the practical use of R for these is explained and laid out. R code examples, many with output, are embedded throughout the text. Epidemiology with R is an advanced textbook suitable for senior undergraduate and graduate students, professional researchers, and practitioners in the fields of human and non-human epidemiology, public health, veterinary science, and biostatistics.

This chapter describes survival analysis. Survival analysis concerns data where the outcome is a length of time, namely the time from inclusion in the study (such as diagnosis of some disease) till death or some other event — hence the term 'time to event analysis', which is also used. There are two primary targets normally addressed in survival analysis: survival probabilities and event rates. The chapter then looks at the life table estimator of survival function and the Kaplan–Meier estimator of survival. It also considers the Cox model and its relationship with Poisson models, as well as the Fine–Gray approach to competing risks.

This chapter explores the problems caused by categorizing quantitative variables (here termed continuous variables). Optimum decisions are made by applying a utility function to a predicted value. At the decision point, one can solve for the personalized cutpoint for predicted risk that optimizes the decision. Dichotomization on independent variables is completely at odds with making optimal decisions. To make an optimal decision, the cutpoint for a predictor would necessarily be a function of the continuous values of all the other predictors. Moreover, categorization assumes that the relationship between the predictor and the response is flat within intervals; this assumption is far less reasonable than a linearity assumption in most cases. Categorization of continuous variables using percentiles is particularly hazardous. To make a continuous predictor be more accurately modelled when categorization is used, multiple intervals are required.

ObjectivesAbdominal fat has been identified as a risk marker of cardiometabolic disease independent of overall adiposity. However, it is not clear whether there are ethnic disparities in this risk. We investigated the associations of visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) with cardiometabolic risk factors in three ethnic diverse populations of Inuit, Africans and Europeans.DesignCross-sectional pooled study.SettingGreenland, Kenya and Denmark.MethodsA total of 5113 participants (2933 Inuit, 1397 Africans and 783 Europeans) from three studies in Greenland, Kenya and Denmark were included. Measurements included abdominal fat distribution assessed by ultrasound, oral glucose tolerance test, hepatic insulin resistance, blood pressure and lipids. The associations were analysed using multiple linear regressions.ResultsAcross ethnic group and gender, an increase in VAT of 1 SD was associated with higher levels of hepatic insulin resistance (ranging from 14% to 28%), triglycerides (8% to 16%) and lower high-density lipoprotein cholesterol (HDL-C, −1.0 to −0.05 mmol/L) independent of body mass index. VAT showed positive associations with most of the other cardiometabolic risk factors in Inuit and Europeans, but not in Africans. In contrast, SAT was mainly associated with the outcomes in Inuit and Africans. Of notice was that higher SAT was associated with higher HDL-C in African men (0.11 mmol/L, 95% CI: 0.03 to 0.18) and with lower HDL-C in Inuit (−0.07 mmol/L, 95% CI: -0.12 to –0.02), but not in European men (−0.02 mmol/L, 95% CI: −0.09 to 0.05). Generally weaker associations were observed for women. Furthermore, the absolute levels of several of the cardiometabolic outcomes differed between the ethnic groups.ConclusionsVAT and SAT were associated with several of the cardiometabolic risk factors beyond overall adiposity. Some of these associations were specific to ethnicity, suggesting that ethnicity plays a role in the pathway from abdominal fat to selected cardiometabolic risk factors.

Background and aim: Both micro- and macro vascular complications represent major problems for diabetes patients and monitoring of the extent of these among diabetes patients is essential. Several studies have reported decreasing complications rates. We describe the burden and trend in 18 groups of complications in persons with diabetes in Denmark 1996-2016. Methods: We compiled a diabetes register for the entire Danish population, including reliable classification of type of diabetes. From the National Patient Register we extracted dates of recorded complications in 18 classes. Binomial regression was used to describe the prevalence of complications at diagnosis and change in these over time. Rate models based on Poisson likelihood were used to describe the incidence rates and changes in these. Analyses were conducted separately for T1D and T2D, and controlled for sex, age, duration of diabetes and including a linear term to describe the calendar time effect (date of diagnosis). Results: The prevalence at diagnosis of previous CVD was 10% in T1D and 37% in T2D, with annual relative changes of 3% in T1D and 5% in T2D. Retinopathy prevalence at diagnosis was 4.3% in T1D and 1.7% in T2D with no change in T1D, but a relative decrease of 6% in T2D. We found similar decreases in rates of complications in T1D and T2D; decrease of 2%/year in rates of CVD, 5%/year in amputations, while there were no changes in the incidence rates of retinopathy and renal disease over the period 1996-2016. For most complications we found a very high incidence during the first year after diagnosis, most likely reflecting a diagnostic catch-up and not any biological phenomenon. Conclusions: A steady decrease in incidence rates of most complications was seen, but not for microvascular complications. The pattern of complications at diagnosis was more mixed, influenced by fluctuations in diagnostic activity over the period. In general an encouraging trend in complication occurrence was seen in Denmark in the period 1996-2016. Disclosure B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. H. Amadid: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

Background: Lipid-lowering treatment is crucial in preventing cardiovascular disease in type 2 diabetes subjects. It is unknown how well treatment guidelines translate into clinical practice. We examined measured lipid levels in relation to use of lipid-lowering drugs among type 2 diabetes subjects in Denmark from 2010 to 2017. Methods: The study population consisted of 404,389 subjects with type 2 diabetes living in Denmark between 1996 and 2017 identified using the Danish Diabetes Register. Redemptions of prescribed lipid-lowering drugs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels was sourced from the National Laboratory Database containing detailed information on laboratory measurements at major clinical laboratories since 2010. A drug-exposure function was developed and applied to examine follow-up of lipid-lowering drug coverage at any given time based on the redeemed amount and dose of lipid-lowering drugs. Annual mean lipid levels were obtained by calculating the mean lipid measurement value per subject, per calendar year, and per lipid type. Proportions of subjects within LDL thresholds were calculated according to thresholds defined by 2019 European Society of Cardiology dyslipidemia guidelines. Results: In total, 64% of subjects redeemed at least two prescriptions of lipid-lowering drugs during the study period. A decline in levels of total-cholesterol and LDL was observed in the years from 2010 to 2017 in users and non-users of lipid-lowering drugs. Annual mean LDL levels were lower among lipid-lowering drug users compared with non-users (in 2017: 1.84 and 2.57 mmol/L, respectively). A greater fraction of lipid-lowering drug users achieved the LDL goal of Conclusions: Lipid-lowering drug use and LDL levels are far from optimal in the Danish type 2 diabetes population and constitute a large potential for improvement. Disclosure H. Amadid: None. M. Bekker-Nielsen Dunbar: None. P.F. Rønn: Research Support; Self; Amgen, Danish Diabetes Academy. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J.S. Knudsen: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Amgen Inc.

Background: Non-western (non-w) migrants in Europe are at increased risk of type 2 diabetes (T2D) but it is not known if this translates into increased risk of atherosclerotic cardiovascular disease (ASCVD). We calculated age- and sex-specific incidence rates (IR) of ASCVD following T2D among 1st generation migrants in Denmark compared with Danish-born citizens. Methods: Data were obtained from nationwide registers. A total of 346,947 people diagnosed with T2D between 1997-2016 were followed for a median (IQR) of 6.7 (8.8) yr, and classified as Danish-born citizens, western- or non-w migrants according to country of birth. IR of first ASCVD event and death from other causes were estimated separately using Poisson regression with risk time as offset, adjusting for T2D duration and education. Results: Non-w migrants (n=27,693) were younger at T2D diagnosis than Danish-born (mean [SD], 50.8 [11.8] vs. 61.6 [13.5] yr). In total, 104,286 persons (30.1%) developed ASCVD. In adjusted models, ASCVD rates were higher for non-w migrant women at 40-60 yr but lower for both genders at 60-80 yr, compared to western migrants and Danish-born (Figure 1A-B). Non-ASCVD related mortality was also lower among non-w migrants (Figure 1C). Conclusion: Non-w migrants had lower risk of developing ASCVD at 60-80 yr and lower mortality from other causes. This may reflect a ’healthy migrant effect’ or differences in lifestyle or medication. Disclosure G.S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. S. Byberg: None. A.D. Bjørkman: None. A.A. Isaksen: Research Support; Self; Novo Nordisk Foundation. H. Amadid: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

IntroductionThe objective of this study was to give an overview of prevalence, incidence and mortality of type 1 (T1D) and type 2 diabetes (T2D) in Denmark, and their temporal trends.Research design and methodsWe constructed a diabetes register from existing population-based healthcare registers, including a classification of patients as T1D or T2D, with coverage from 1996 to 2016. Using complete population records for Denmark, we derived prevalence, incidence, mortality and standardized mortality ratio (SMR).ResultsThe overall prevalence of diabetes at 2016 was 0.5% for T1D and 4.4% for T2D, with annual increases since 1996 of 0.5% for T1D and 5.5% for T2D. Incidence rates of T1D decreased by 3.5% per year, with increase for persons under 25 years of age and a decrease for older persons. T2D incidence increased 2.5% per year until 2011, decreased until 2014 and increased after that, similar in all ages. The annual decrease in mortality was 0.3% for T1D and 2.9% for T2D. The mortality rate ratio between T1D and T2D was 1.9 for men and 1.6 for women. SMR decreased annually 2% for T1D and 0.5% for T2D.ConclusionsIncidence and prevalence of diabetes is increasing, but mortality among patients with diabetes in Denmark is decreasing faster than the mortality among persons without diabetes. T1D carries a 70% higher mortality than T2D.

Background Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM). Methods The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed. Results After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI − 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference − 0.33 V (95% CI − 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA1c did not confound the associations. Conclusions Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA1c. Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H–D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Aims To examine the incidence rates of any and referable diabetic retinopathy (DR) among migrants in Denmark. Methods Nationwide clinical data on diabetes patients followed since 2005 were analysed. Patients were classified according to country of origin into six groups: Denmark, other Europe, Sub Saharan Africa, Middle East/North Africa, Asia, and America/Oceania. A total of 93,780 or 110,897 patients without any (including unspecific diagnoses) or referable (proliferative) DR at baseline were analyzed. We estimated event rates and hazard ratios (HRs) for incidence of any and referable DR according to country of origin. Results After an average follow-up of 3.59 years 6727 had incident any DR and 4747 patients had referable DR. Compared to people of Danish origin, migrants from the Middle East/North Africa and Asia had a higher risk of any and referable DR after adjustment for age, sex, body mass index, smoking status, types and duration of diabetes, clinic type (general practice vs outpatient clinic), HbA1c, blood pressure and lipid levels. The associations remained significant after further adjustment for frequency of eye screening. Conclusions Migrants from the Middle East/North Africa and Asia were at increased risk of developing any and referable DR compared to native Danes, and these differences were not fully explained by differences in underlying clinical, diabetic and cardiometabolic risk factors.