Global epidemiology of type 1 diabetes in young adults and adults: a systematic review

1The worldwide epidemiology of childhood Type 1 diabetes (T1D) was extensively described in the 6th edition of the International Diabetes Federation (IDF). Data were retrieved in approximately 45% of the countries. In contrast, we are unaware of a similar review on the worldwide epidemiology of adult T1D diabetes, although T1D is known to occur even late in adults. A major limitation of the epidemiology of T1D in adults is certainly the difficulty there is to distinguish it from Type 2 diabetes (T2D) requiring insulin treatment or from Latent Autoimmune Diabetes in Adults (LADA), when specific markers of autoimmunity are not searched.

2Here, our primary objective was to describe – through a systematic review of the literature – the available published information on adult T1D incidence, and the diagnostic criteria used for case definition. A secondary objective was to study how the variations of T1D incidence in adults mirrored those in children.

3A systematic review was conducted according to the PRISMA recommendations to retrieve original papers published in English, French and Spanish up to November 6th, 2014, in peer-reviewed journals reporting the incidence of T1D among individuals aged more than 15 years, in population-based studies (i.e. collected in a defined geographic area) and reporting the diagnostic criteria used to define T1D.

4The databases used for the literature search were Medline (PubMed), Google Scholar and Thomson Reuters (Web of Knowledge). The protocol of the search was registered in the International Prospective Register of Systematic Reviews (PROSPERO) and is available on http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42012002369 (Registration number: 2012:CRD42012002369). Figure 1 presents the flow diagram of the bibliographic search, Additional file 1 for the full electronic search strategy, and Additional file 2 for the PRISMA checklist.

5For each study, the following information was extracted:the identification of the study: authors, title, journal, publication year,the period and country of study. The country was categorized by its World Health Organization (WHO) region and economic level: high-income (HIGH) or low- and middle-income (LMIC),the geographic coverage of the study: nationwide (when the study was performed in the entire nation) and local (when it was restricted to a given region, city, or a geographically defined population),the diagnostic criteria used to define T1D in adults: detection of autoantibodies against beta-cells (such as: islet cell antibody (ICA), insulin autoantibody (IAA), islet antigen-2 autoantibody (IA-2), anti-glutamic acid decarboxylase antibodies (GAD)), measurement of the fasting C-peptide level, need for permanent insulin therapy, time when the administration of insulin therapy was started, and clinical signals of T1D diabetes such as ketosis, ketonuria and weight loss,the sources of data/registers reporting T1D incidence in the studies, defined according to LaPorte et al. as: primary source of information: a “well-established system of standardized registries for identifying new cases”, for example national or regional registers, secondary source of information: other different sources of cases “that would provide a check on the degree of ascertainment”, for example medical records or hospital discharges, and tertiary source of information: a third approach for identifying cases, for example, through surveillance system or death certificates,the reported percentage of completeness/ascertainment between sources of information reporting incidence,the incidence rates reported in the text, tables or graph (expressed as new cases per 100.000 persons/year) by sex and age classes,additional information such as those concerning rural/urban, or ethnic differences.

6the identification of the study: authors, title, journal, publication year,

7the period and country of study. The country was categorized by its World Health Organization (WHO) region and economic level: high-income (HIGH) or low- and middle-income (LMIC),

8the geographic coverage of the study: nationwide (when the study was performed in the entire nation) and local (when it was restricted to a given region, city, or a geographically defined population),

9the diagnostic criteria used to define T1D in adults: detection of autoantibodies against beta-cells (such as: islet cell antibody (ICA), insulin autoantibody (IAA), islet antigen-2 autoantibody (IA-2), anti-glutamic acid decarboxylase antibodies (GAD)), measurement of the fasting C-peptide level, need for permanent insulin therapy, time when the administration of insulin therapy was started, and clinical signals of T1D diabetes such as ketosis, ketonuria and weight loss,

10the sources of data/registers reporting T1D incidence in the studies, defined according to LaPorte et al. as: primary source of information: a “well-established system of standardized registries for identifying new cases”, for example national or regional registers, secondary source of information: other different sources of cases “that would provide a check on the degree of ascertainment”, for example medical records or hospital discharges, and tertiary source of information: a third approach for identifying cases, for example, through surveillance system or death certificates,

11the reported percentage of completeness/ascertainment between sources of information reporting incidence,

12the incidence rates reported in the text, tables or graph (expressed as new cases per 100.000 persons/year) by sex and age classes,

13additional information such as those concerning rural/urban, or ethnic differences.

14The country distribution of the T1D incidence information and the analysis of the diagnostic criteria used were performed on the entire set of articles retrieved. For the few papers for which the results were presented by ethnic origin, we estimated the mean value of the incidence for the given period in the countries/regions concerned.

15In the geographical correlation analyses between children and adult incidences, we considered for each country the more recent nationwide study published, or if not available, the last published set of local studies retrieved from a given area in the country; in addition, we included all published papers reporting auto-antibodies against beta-cells or C-peptide. To obtain an estimate of the incidence of T1D in children in the countries for which the adult incidence was available, we used the data provided by the same adult paper, when available. The incidence of T1D in children was not available in 9 of these papers included in the geographical correlation analyses. In this case, it was estimated through a separate systematic review focused on the corresponding countries and periods (see Additional file 3).

16Data were extracted from graphs using GraphClick.

17The country-to-country co-variation of children and adult incidences was quantified by the Spearman correlation and a linear regression.

18The R software (version 3.0.1) was used for statistical and graphic analyses.

19Seventy articles reporting incidence of T1D in young adults and adults aged over than 15 years concerned one country, and one article concerning two countries were retrieved in this systematic review, resulting in a total of 71 studies covering 35 countries (Table 1). Twenty-four of the 71 studies were nationwide; 43 papers provided information on the T1D incidence in the age class 15–29 years, 26 in the age class 30–59 years, and 6 in the persons aged >60 years.

20A primary source of information was reported in 99% (70 of 71) of the studies: among these reported sources, 60% (42 of 70) were from medical/hospital records, 36% (25 of 70) from national or regional registers, and 4% (3 of 70) from other sources, such as community-based surveys; a secondary source of information was reported in 90% (64 of 71) of the studies: among these reported sources, 58% (37 of 64) were from medical/hospital records, 16% (10 of 64) from associations of patients, 14% (9 of 64) from drug or supplies prescription registers, 8% (5 of 64) from national or regional registers, and 5% (3 of 64) from death certificates and schools registers; finally, a tertiary source of information was reported in 21% (15 of 71) of the studies: among these reported sources, 27% (4 of 15) were from national or regional registers, 27% (4 of 15) from associations of patients, 20% (3 of 15) from death certificates, 20% (3 of 15) from drug or supplies prescription registers, and 7% (1 of 15) from medical registers; see details in Table 1. Percentage of ascertainment (completeness) between sources of information was evaluated in 53 of 71 (75%) studies. The mean percentage of ascertainment of these 53 studies was 94% (Table 1).

21In the group of young adults (15–19), the lowest incidence of T1D was reported in Mauritius, (1.1/100.000 persons/year), and the highest in Estonia (39.9/100.000 persons/year). In the 70–79 year age group, the lowest incidence was reported in Navarra, Spain (0.8/100.000 persons/year) and the highest in Kronoberg, Sweden (55/100.000 persons /year). The details of all retrieved incidence by study and age classes are in Additional file 4: Table S1.

22Autoantibodies against beta-cell antigens or the C-peptide were included in the T1D diagnostic criteria in 14 studies, detection of ICAs was reported in 9 studies, IAA in 4 studies, IA2 in 5 studies, and GAD in 11 studies. The C-peptide was measured in 7 studies. In one paper difference of auto-antibodies by age group (0–19) was explored but no significant differences were detected. The other reported diagnostic criteria for T1D were the need for insulin therapy (reported in 70 of 71 studies), clinical symptoms of diabetes (reported in 56 of 71 studies), low or normal body weight (14 of 71 studies), and ketosis or ketonuria (26 of 71 studies). The details are shown in Table 1.

23The variations of incidence of T1D in adults with country and age were studied in each area for which we retrieved information on a geographically defined population. This concerned 35 countries.

24In 23 out of 35 (66%) countries (55 of 71 studies), the incidence of T1D was higher in the age range of 0–14 compared with 15–19 years. When restricted to the 14 reports for which the criteria of diagnosis of T1D were auto-antibodies against beta-cells or C-peptide detection, the variation of adult incidence with age showed a consistent decrease after the age of 14 years (Figure 2 and Additional file 4: Table S1).

25A significant geographical correlation, as measured by the Spearman correlation coefficient, was found between adult T1D incidence and 0–14 incidence in the age classes 15–19 years, 20–24 years, 25–29 years, 30–34 years and overall in the entire 15–60 group (r = 0.75, p-value: 5.7 × 10−10). The correlation was not significant in the oldest class where sparse data were available, but the relation was similar (Figure 3).

26T1D incidence was larger in males aged 15 to 39 years than in females in 44 (81%) of the 54 studies reporting incidence by sex (Additional file 5: Table S2). The mean male-to-female ratio in our review was 1.47 (95% CI for mean 1.33-1.60, SD = 0.49, n = 54, p = < 0.0001).

27A first result of this systematic review is the paucity of data available on adult incidence of T1D as compared to those concerning children. The 71 studies retrieved provided information on adult T1D in only 35 countries, 40% of the 88 countries with primary childhood T1D incidence information in the 6th IDF atlas.

28A second result is that only a small proportion (n = 14) of the 71 studies used detection of specific autoantibodies and/or dosage of C-peptide as diagnostic criteria of adult T1D.

29A third result was that in a majority of the retrieved studies, adult T1D incidence was greater in men than in women, which contrasts with incidence of T1D in children where sex ratio is around one. Using comparative data, Karvonen et al. also described a male excess among young adults in the 15–39 years of age. Sex differences in exposure to possible environmental triggers of T1D, in hormonal/genetic susceptibility, in lifestyle have been proposed as possible explanations for this difference.

30A last striking observation of the current analysis is the strong geographical correlation of the incidences in adults and children. This correlation may be explained by the fact that adults with T1D share the gene alleles known to be associated to incidence of T1D in children,, and/or some predisposing environmental causes. For example, in a previous study on incidence of T1D in children, a significant positive correlation was detected between the percentage of urban population and the incidence of T1D in children (r = 0.41 p-value: < 0.0001); in this review a significantly higher urban proportion of T1D incidence among adults was found in 4 of the 7 studies reporting differences between rural vs urban areas.

31There was an overall decrease of incidence with age in adults and young adults after the age of 14. A second peak of T1D around the age of 50, as described by Krolewski et al., was only reported in 7% (4 of 58) of the studies.

32The paucity of data made it impossible to document an increase in adult T1D incidence that would parallel the dramatic increase observed in children. Indeed, successive studies in the same region over different periods reporting incidence in people aged >30 years of age were only found for Belgium, Lithuania and Sweden. Similarly, this review did not dispose of sufficient data to document differences in the clinical presentation of T1D of adults and children as suggested elsewhere; indeed only two of the 71 studies describe differences in clinical presentation of T1D between adults and children.

33Improving the quantity and quality of information on adult T1D is not only useful to better understand the epidemiology and natural history of T1D, but can have practical consequences, as delay of T1D diagnosis may mean retardation in insulin treatment, lost opportunities for potential prevention of acute and chronic complications, and even death: in Croatia, 14% of the incident cases were identified solely through death certificates, and high mortality was found in the newly-diagnosed T1D aged over 50.

34Overall, the results of this systematic review should encourage the launching of epidemiological studies of adult T1D with specific diagnostic criteria.

35All the supporting data are included as additional files.