Trends in type 2 diabetes mellitus disease burden in European Union countries between 1990 and 2019

This observational study aimed to assess trends in type 2 diabetes mellitus (T2DM) disease burden in European Union countries for the years 1990–2019. Sex specific T2DM age-standardised prevalence (ASPRs), mortality (ASMRs) and disability-adjusted life-year rates (DALYs) per 100,000 population were extracted from the Global Burden of Disease (GBD) Study online results tool for each EU country (inclusive of the United Kingdom), for the years 1990–2019. Trends were analysed using Joinpoint regression analysis. Between 1990 and 2019, increases in T2DM ASPRs were observed for all EU countries. The highest relative increases in ASPRs were observed in Luxembourg (males + 269.1%, females + 219.2%), Ireland (males + 191.9%, females + 165.7%) and the UK (males + 128.6%, females + 114.6%). Mortality trends were less uniform across EU countries, however a general trend towards reducing T2DM mortality was observed, with ASMRs decreasing over the 30-year period studied in 16/28 countries for males and in 24/28 countries for females. The UK observed the highest relative decrease in ASMRs for males (− 46.9%). For females, the largest relative decrease in ASMRs was in Cyprus (− 67.6%). DALYs increased in 25/28 countries for males and in 17/28 countries for females between 1990 and 2019. DALYs were higher in males than females in all EU countries in 2019. T2DM prevalence rates have increased across EU countries over the last 30 years. Mortality from T2DM has generally decreased in EU countries, however trends were more variable than those observed for prevalence. Primary prevention strategies should continue to be a focus for preventing T2DM in at risk groups in EU countries.

for all 28 countries studied. The highest 2019 DALYs for both sexes were observed in the Czech Republic (1190.5/100,000 for males, 859.5/100,000 for females). The lowest 2019 DALYs were observed in both sexes in France (332.3/100,000 for males, 231.7/100,000 for females). In 2019, Male DALYs were higher than female DALYs in all 28 countries.
Trends in T2DM mortality. Male ASMRs decreased in 16 of the 28 countries over the 30-year study period.
For females, ASMRs decreased in 24 countries. The largest relative increases in ASMR between 1990 and 2019 in males and females were observed in Latvia (+ 82.5% for males, + 55.1% for females). The largest relative decrease in ASMR for males from 1990 to 2019 was in the UK (-46.9%). In females, the largest relative decreases in ASMR was identified in Cyprus (−67.6%). Females in the UK observed a −47.1% reduction in ASMRs over the period. This data can be found in Supplementary Tables 1a and 1b Trends in T2DM disability-adjusted life years. Relative reductions in DALYs were observed in 3 of 28 countries for males (Cyprus, Malta and the Netherlands), and 11 of 28 countries for females. The greatest relative increase in DALYs was observed in Luxembourg for males (+ 99.3%), and the UK for females (+ 35.9%). The largest relative reduction in DALYs was observed in Cyprus for both sexes (− 26.2% for males, − 31.2% for females). Data are presented in Supplementary Tables 1a and 1b. Joinpoint analysis for T2DM mortality. Sex-specific Joinpoint regression analyses for T2DM ASMRs between 1990 and 2019 are displayed in Fig. 2, and Tables 1 and 2. Significant ASMR estimated annual percentage changes (EAPCs) for each trend are presented (p value < 0.05). Trends in ASMRs varied both between and within countries. The single greatest increase in ASMR was observed in Slovenia for both sexes (EAPC + 14.4% for males between 1990 and 1994 and + 7.6% for females between 1990 and 1996). Slovenia also reported the single greatest reductions in ASMRs in both sexes (EAPC − 11.1% for males between 2003 and 2009 and − 12.2% for females between 2002 and 2009). No country observed persistently positive trends, for either sex. Persistently negative Joinpoint trends between 1990 and 2019 in ASMR were observed in Finland, Italy, Luxembourg and Spain for males, and in Cyprus, Ireland, Luxembourg, Malta and Spain for females. For both sexes, data for the UK demonstrates significant decreases in ASMR EAPCs from 1990 to 2011, followed by a plateau to insignificant EAPCs observed until 2019. Joinpoint analysis for T2DM prevalence. Sex-specific Joinpoint regression analyses for T2DM ASPRs between 1990 and 2019 are displayed in Fig. 3, and Tables 3 and 4. Significant ASPR EAPCs are presented (p value < 0.05). Increasing trends in T2DM prevalence were observed in all countries for both sexes. The rate of increase in ASPR varied across and within countries. Consistent, significantly positive trends were observed in 12 of the 28 countries in males, and in 11 countries in females. Over the time period studied, the most rapidly increasing ASPRs in males were observed in Poland (2005-2010 EAPC + 6%), Hungary (2017-2019 EAPC + 6%) and Luxembourg (2000-2010 EAPC + 6%). For females, the most rapidly increasing ASPRs for T2DM were observed between 2017 and 2019 in Ireland (EAPC + 6.8%) and Luxembourg (EAPC + 8.8%). The UK observed consistent, significantly positive increases in T2DM ASPRs from 1996/7-2015 for both males and females (EAPC increases of + 3.2% to + 5.0%), followed by a plateau from 2015, where non-significant EAPCs of

Discussion
In this observational analysis of trends in the disease burden of T2DM in EU countries, we identify increasing prevalence of T2DM across all 28 EU countries between 1990 and 2019, with the highest relative increases in T2DM prevalence observed in the UK, Luxembourg and Ireland for both sexes. Over the same 30-year study period, mortality trends generally decreased across EU countries, however, the trends were less uniform than those observed for prevalence.
Being aware that the present study is observational, we are cautious to not attribute causality to the identified trends, however probable contributors to the increases in T2DM prevalence over the study period include ageing populations, increased diagnostic testing for diabetes and an increasing prevalence of obesity [12][13][14] . The general reductions in T2DM mortality trends observed in this analysis are also likely contributory to the increasing prevalence trends.
These findings suggest that an ongoing public health target should be at primary prevention of T2DM. UK primary care-based screening studies have demonstrated that screening for T2DM identifies 9% of adults with impaired glucose regulation, which represents a state with an increased risk of T2DM and increased mortality 15, 16 . Screening for diabetes is also cost effective 17 . Furthermore, evidence from Finland, the UK, the Netherlands and the US has demonstrated the feasibility and efficacy of T2DM prevention programmes [18][19][20] . The Finnish Diabetes Prevention Study was a randomised controlled trial with four-year follow-up conducted in Finland, which demonstrated a 58% reduction in the risk of T2DM in individuals with impaired glucose tolerance at the end of follow-up in the intervention group compared with controls 18 . The intervention consisted of targeted counselling aimed at reducing weight, reducing fat intake and increasing physical activity. Similarly, a randomised controlled trial of 102 participants with impaired glucose tolerance in the UK, demonstrated an overall reduction in the incidence of T2DM of 55% in the intervention group (receiving targeted motivational interviewing aimed at weight reduction, increased physical activity and reduction of fat intake) when compared with controls over the 3-year study period 21 . Both of the aforementioned randomised controlled trials concluded that T2DM can be prevented in at risk individuals by changes in lifestyle. Despite this, there appears to have been a time lag in the widespread translation of this evidence into clinical practice across the UK and the EU. In 2014, the NHS Diabetes Prevention Programme (NHS DPP) was announced 22 . The programme targets adults in England at risk of T2DM (i.e. with non-diabetic hyperglycaemia), offering evidence-based behavioural interventions (focussed specifically on weight loss, diet and physical activity) in a face-to-face group setting over a minimum of 9 months' duration. The NHS DPP was rolled out nationally in June 2016 and early outcomes have demonstrated favourable results with widespread engagement. By December 2018, 324,699 referrals to the programme had been made with 152,294 individuals attending the initial assessment 23 . Of the 17,252 individuals who had completed the assessment by December 2018, a mean weight loss of 2.3 kg (95% confidence intervals 2.2-2.3 kg) and mean HbA1C reduction of 1.26 mmol/mol (95% confidence intervals 1.20-1.31 mmol/mol) was identified 23 . The joinpoint analysis for T2DM prevalence performed and presented in this study demonstrates plateauing T2DM prevalence rates since 2015/16-2019 in the UK, with estimated annual percentage increases down to insignificant + 0.9% for males and 0% for females.
The high overall relative increases in prevalence observed in the UK since 1990 may in part be explained by the UK having the largest T2DM mortality reductions of all EU countries for males. There are numerous examples of how a death would be directly attributed to diabetes and registered as such within the GBD Study database: an example provided by the GBD collaborators is a death resulting from acute renal failure, which was caused by a hyperosmolar hyperglycaemic state in an individual with T2DM 24 . The reductions in mortality observed in the UK within the present study were consistent with previous evidence derived from alternative data sources, including The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) [25][26][27] . Being cautious not to infer causality, we suggest that likely contributors to the observed reductions in mortality rates include the improved medical management of the disease once diagnosed, as well as earlier diagnosis and a resultant higher prevalence of early disease. The joinpoint regression analysis performed in the present analysis demonstrates recent plateaus in mortality rates from T2DM in males and females in the UK between 2011 and 2019: explanations for these trends are lacking and should be a focus of future research.
Reducing trends in T2DM mortality were also observed in the majority of the other EU countries between 1990 and 2019, however, trends were less uniform than those observed for prevalence. Indeed, ASMRs increased over the 30-year period studied in 11/28 countries for males and in 4/28 countries for females. Chen et al. 28 analysed trends in all-cause mortality amongst patients with diabetes (both type 1 and type 2) using data obtained from 35 observational studies identified through systematic review methodology, and identified reductions in all cause mortality rates in the majority of Europid populations with diabetes from 2000 to 2016. The authors also identified that the magnitude of annual mortality reduction matched or exceeded that observed in people   www.nature.com/scientificreports/ without diabetes in nearly 60% of populations studied which reflects well upon the evolving management of individuals diagnosed with diabetes. The data presented in Chen et al.'s systematic review study differs from that derived from the GBD study database in that they do not differentiate between type 1 and type 2 diabetes; they do not isolate mortality resulting directly from diabetes (and instead included all-cause mortality in individuals with diabetes), and they do not include data later than 2016. Despite these methodological differences, both studies identify similar trends towards the majority of Europid populations having reductions in overall mortality over recent decades. To our knowledge, this is the first paper to compare T2DM prevalence, mortality and DALYs rates across EU countries using data obtained from the 2019 GBD Study. There are, however, several limitations which must be considered when appraising the results of this observational study. Firstly, there may be some inconsistencies both within and between countries when a cause of death is assigned. This is particularly true when considering chronic health conditions like T2DM, as accuracy of cause of death may be confounded by other co-morbidities. However, the quality of health data reporting from the EU countries and the UK is assessed and graded by the GBD Study as discussed in the methodology section of the manuscript, and corrections are made for underregistration. Additionally the GBD uses garbage code redistribution algorithms to improve comparability and reliability ('garbage' codes allude to deaths attributed to poorly-defined diagnoses or conditions that cannot be the single underlying cause of death) 3,4 . Secondly, the data obtained is applicable solely for identification and comparison purposes of T2DM across EU countries and, as such, causal relationships cannot be drawn. Third, we accept that changes in coding practices (notably from ICD-9 to ICD-10), as well as changes in the WHO definition of T2DM which occurred during the observation period, may compromise the robustness of the presented data 29 . The GBD maps deaths to causes lists as an attempt to correct for changes in coding systems 30 . Finally, we acknowledge that confounding variables beyond the scope of discussion will have differential effects by country on the data presented from this observational study: using sex-specific, age-standardised mortality, prevalence and DALY rates attempts to account for some of the inevitably confounding variables.

Conclusion
In summary, there have been general increases in T2DM DALYs and prevalence across EU countries between 1990 and 2019, which have been accompanied by trends towards a reduction in T2DM mortality. Public health measures should continue to focus on primary prevention of T2DM, given its significant costs, morbidity and mortality to affected populations.