Introduction
More than 1 million adults in the UK and 160,000 adults in Sweden are estimated to be living with undiagnosed diabetes [
1], which is potentially detectable by screening. In screening for type 2 diabetes, one cluster-randomised controlled trial in a high-risk UK population (Anglo–Danish–Dutch study of intensive treatment in people with screen-detected diabetes in primary care [ADDITION]-Cambridge [
2]) and a controlled trial in a high-risk Danish population (ADDITION-Denmark [
3]) found no effect on mortality in the population after approximately 10 years. One cohort study in an average-risk UK population (the Ely cohort) reported a reduction of mortality in 1990–1999, but no effect 10 years later [
4]. In the Ely cohort, the average lead time for a diabetes diagnosis following screening was estimated at 3.3 years, but this was not associated with lower incidence of adverse health outcomes for individuals detected earlier through screening [
5]. A study in Sweden compared people with diabetes detected through an opportunistic screening programme with those detected clinically in the same eligible population and found no difference in age at diagnosis or any effect on health outcomes for screen-detected individuals [
6]. However, in ADDITION-Denmark, a lead time of 2.2 years was associated with lower mortality and cardiovascular disease (CVD) risk among those in the screened group [
7].
One review found that the positive predictive values of a single biochemical screening test for diabetes ranged between 24% and 48% [
8], meaning that more than half of those with positive screening tests probably have only transient non-diabetic hyperglycaemia. Although it is known that, compared with normoglycaemia, those with non-diabetic hyperglycaemia have an increased risk of CVD and death [
9], the fate of those with unconfirmed diabetes following a positive test result has not specifically been studied.
Following reports in the 1970s of relatively high mortality from CVD in the Swedish county of Västerbotten, a community public health intervention programme was launched [
10]. The Västerbotten Intervention Programme (VIP) was first implemented in 1985 and reached full coverage in 1992. There is some evidence that the overall public health programme has had a positive impact on all-cause and CVD mortality [
11]. VIP has both a community and an individual focus, with invitations to standardised health examinations in primary healthcare [
10]. Crucially, these include OGTTs, which allows us to study the VIP as a model for an organised systematic universal diabetes population screening programme.
We aimed to investigate the association between screen detection of type 2 diabetes and all-cause mortality, CVD events, renal disease and retinopathy in this population-based cohort of adults eligible to be screened at 10 year intervals. The secondary aim was to investigate the rate of these outcomes in unconfirmed screen-positive cases.
Results
We identified 9666 diabetes cases in total, constituting a cumulative incidence of 6.9% in the study population. Those with screen-detected diabetes were on average 4.6 years younger at diagnosis than those with clinically detected diabetes, 6.4 years younger than clinically detected individuals who were screening participants and 2.8 years younger than clinically detected individuals who were screening non-participants (Table
1). There was a substantial difference in the proportion of individuals who had experienced a CVD event prior to the date of detection of diabetes between those who had screen-detected diabetes (5.4%) and those with clinically detected diabetes (15. 2%). Among all individuals with clinically detected diabetes, 227 (2.6%) had a CVD event recorded on the same date as the date of detection of diabetes (data not shown).
Table 1
Descriptive statistics of participants with type 2 diabetes mellitus, VIP 1992–2013
Total | 11,069 (100.0) | 1024 (9.3) | 1403 (12.7) | 8642 (78.1) | 4506 (40.7) | 4136 (37.4) |
Men | 6459 (58.4) | 595 (58.1) | 783 (55.8) | 5081 (58.8) | 2572 (57.1) | 2509 (60.7) |
Women | 4610 (41.6) | 429 (41.9) | 620 (44.2) | 3561 (41.2) | 1934 (42.9) | 1627 (39.3) |
Age at detection, years |
Mean ± SD (median) | 58.5 ± 9.7 (59.9) | 55.1 ± 6.4 (59.8) | 53.4 ± 8.0 (59.7) | 59.7 ± 9.9 (60.2) | 61.5 ± 9.0 (62.2) | 57.9 ± 10.4 (58.4) |
30–39 | 246 (2.2) | 0 (0.0) | 27 (1.9) | 219 (2.5) | 20 (0.4) | 199 (4.8) |
40–49 | 1410 (12.7) | 82 (8.0) | 220 (15.7) | 1108 (12.8) | 441 (9.8) | 667 (16.1) |
50–59 | 3296 (29.8) | 335 (32.7) | 406 (28.9) | 2555 (29.6) | 1222 (27.1) | 1333 (32.2) |
60–69 | 4494 (40.6) | 607 (59.3) | 750 (53.5) | 3137 (36.3) | 1851 (41.1) | 1286 (31.1) |
70+ | 1623 (14.7) | – | – | 1623 (18.8) | 972 (21.6) | 651 (15.7) |
Year of detection |
1992–1999 | 2012 (18.2) | 217 (21.2) | 369 (26.3) | 1426 (16.5) | 352 (7.8) | 1074 (26.0) |
2000–2006 | 3841 (34.7) | 369 (36.0) | 537 (38.3) | 2935 (34.0) | 1426 (31.6) | 1509 (36.5) |
2007–2013 | 5216 (47.1) | 438 (42.8) | 497 (35.4) | 4281 (49.5) | 2728 (60.5) | 1553 (37.5) |
SES in the 1990 censusa
|
Manual workers | 5516 (49.8) | 479 (46.8) | 701 (50.0) | 4337 (50.2) | 2259 (50.1) | 2089 (50.5) |
Non-manual workers | 4235 (38.3) | 411 (40.1) | 543 (38.7) | 3285 (38.0) | 1737 (38.5) | 1534 (37.1) |
Self-employed | 744 (6.7) | 82 (8.0) | 103 (7.3) | 562 (6.5) | 305 (6.8) | 264 (6.4) |
Undefined | 574 (5.2) | 52 (5.1) | 56 (4.0) | 458 (5.3) | 205 (4.5) | 249 (6.0) |
Prior CVD eventb
| 1420 (12.8) | 55 (5.4) | 53 (3.8) | 1312 (15.2) | 673 (14.9) | 639 (15.4) |
Among clinically detected individuals with diabetes who were screening participants, those who had a previous diabetic or non-diabetic hyperglycaemic screening result were diagnosed on average 6.3 and 6.9 years, respectively, after their last screening. Those who had previously had a normoglycaemic screening result were diagnosed with diabetes on average 10.3 years after their last screening; among individuals who had screened negative for diabetes or non-diabetic hyperglycaemia, 13 (0.76%) were diagnosed with diabetes within 1 year (data not shown). Overall, among screening participants, those with screen-detected diabetes had similar mean levels of self-reported bad health and BP to those with clinically detected diabetes and had had a diabetic or non-diabetic hyperglycaemic OGTT result at previous screening (Table
2). For serum total cholesterol, the average levels were also very similar (≤ 0.2 mmol/l difference between confirmed screen-detected diabetes and the other groups), although the differences were statistically significant. Compared with screen-detected diabetes, mean BMI was 1.1 kg/m
2 lower among clinically detected individuals who were screening participants. Among screen-detected individuals with diabetes, 443 (43.3%) reported a family history of diabetes in the VIP questionnaire; the corresponding number was 1519 (33.7%) among clinically detected individuals who were screening participants (data not shown).
Table 2
Characteristics measured at concurrent or previous screening among individuals with type 2 diabetes mellitus who were screening participants, VIP 1992–2013
Age at concurrent or previous screening (years) | 55.1 (6.4) | 53.4 (8.0) | – | 53.4 (7.9) | – | 54.2 (7.3) | – | 54.3 (7.2) | – | 51.9 (8.7) | – |
Time from screening to first register detection (years) | 0.1 (0.2) | – | – | 8.1 (4.9) | – | 6.2 (4.1) | – | 6.9 (4.5) | – | 10.3 (4.9) | – |
BMI (kg/m2) | 30.8 (5.6) | 27.8 (4.8) | < 0.001 | 29.7 (4.7) | < 0.001 | 30.3 (5.0) | 0.048 | 29.9 (4.7) | < 0.001 | 29.1 (4.4) | < 0.001 |
Self-reported overall bad health, n (%) | 397 (38.8) | 459 (32.7) | 0.002 | 1795 (39.8) | 0.741 | 323 (41.6) | 0.455 | 757 (39.9) | 0.588 | 662 (38.6) | 0.993 |
Systolic blood pressure (mmHg) | 140.9 (18.6) | 136.6 (20.5) | < 0.001 | 139.2 (18.7) | 0.010 | 140.8 (19.2) | 0.967 | 140.3 (18.6) | 0.394 | 137.0 (18.4) | < 0.001 |
Diastolic blood pressure (mmHg) | 86.2 (10.6) | 83.2 (11.5) | < 0.001 | 85.2 (11.1) | 0.007 | 86.0 (10.8) | 0.638 | 85.4 (10.6) | 0.051 | 84.3 (11.3) | < 0.001 |
Serum total cholesterol (mmol/l) | 5.6 (1.1) | 5.5 (1.2) | 0.011 | 5.8 (1.2) | < 0.001 | 5.8 (1.2) | 0.002 | 5.7 (1.2) | 0.009 | 5.8 (1.2) | < 0.001 |
The standardised mortality rate was 3.2/1000 person-years for all VIP participants, 8.4/1000 person-years for all non-participants and 3.0/1000 person-years for known normoglycaemic VIP participants (data not shown). Average follow-up time was 8.7 (median 7.8) years for individuals with screen-detected diabetes, and 7.2 (median 6.2) years for those who were clinically detected diabetes, after their date of detection (maximum 21.9 years). Those with screen-detected diabetes had a consistently lower rate of all-cause mortality, CVD, renal disease and retinopathy than those with clinically detected diabetes (Table
3). Among clinically detected individuals with diabetes, screening participants had lower rates of all outcomes compared with screening non-participants. There was a clear pattern of HR; compared with screen-detected diabetes, those who had clinically detected diabetes who were screening participants had an increased risk of poor health outcomes (e.g. all-cause mortality HR 1.70 [95% CI 1.32, 2.18]), and clinically detected individuals who were screening non-participants had an even higher risk of poor health outcomes (e.g. all-cause mortality HR 2.31 [95% CI 1.82, 2.94]) (Table
4). The results were similar over the course of follow-up; a total of 3397 (30.7%) individuals with diabetes, including 394 screen-detected individuals, were followed for 10 years or longer. The HR for all-cause mortality after 10 years was 1.91 (95% CI 1.27, 2.85) for clinically detected vs screen-detected diabetes cases.
Table 3
Crude and standardised incident event and mortality rates among individuals with type 2 diabetes mellitus, VIP 1992–2013
Confirmed screen-detected diabetes | 73 | 8.2 | 4.2 | 128 | 15.5 | 8.7 | 39 | 4.4 | 3.3 | 70 | 8.1 | 6.3 |
Unconfirmed screen-positive individuals | 139 | 10.4 | 5.9 | 141 | 11.0 | 5.8 | 23 | 1.7 | 0.9 | 9 | 0.7 | 0.4 |
Incident clinically detected diabetes | 1330 | 21.4 | 15.5 | 1704 | 30.5 | 21.9 | 649 | 10.8 | 9.3 | 757 | 12.7 | 12.7 |
Screening participants | 515 | 18.8 | 11.5 | 680 | 27.1 | 19.8 | 258 | 9.6 | 8.6 | 279 | 10.5 | 9.7 |
Previous diabetes-indicative OGTT > 1 year before detection | 93 | 17.0 | 9.4 | 114 | 22.9 | 13.7 | 41 | 7.7 | 5.0 | 70 | 13.3 | 9.9 |
Previous non-diabetic hyperglycaemia | 194 | 16.4 | 12.0 | 267 | 24.5 | 21.0 | 100 | 8.7 | 10.5 | 103 | 9.0 | 10.3 |
Previous normoglycaemia | 206 | 22.0 | 12.5 | 275 | 32.3 | 20.4 | 102 | 11.2 | 7.9 | 91 | 10.0 | 8.8 |
Screening non-participants | 815 | 23.4 | 18.4 | 1024 | 33.3 | 25.5 | 391 | 11.6 | 10.2 | 478 | 14.6 | 14.2 |
Table 4
Associations between mode of detection of type 2 diabetes mellitus and death, incident CVD events, renal disease or retinopathy, VIP 1992–2013
Confirmed screen-detected diabetes | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (Ref) |
Unconfirmed screen-positive individuals | 1.35 (1.01, 1.79) | 0.77 (0.60, 0.98) | 0.41 (0.25, 0.69) | 0.08 (0.04, 0.16) |
Incident clinically detected diabetes | 2.07 (1.63, 2.62) | 1.55 (1.29, 1.86) | 2.26 (1.64, 3.13) | 1.66 (1.30, 2.13) |
Screening participants | 1.70 (1.32, 2.18) | 1.25 (1.03, 1.52) | 1.89 (1.34, 2.66) | 1.38 (1.06, 1.80) |
Previous diabetes-indicative OGTT > 1 year before detection | 1.61 (1.18, 2.20) | 1.11 (0.86, 1.43) | 1.58 (1.02, 2.45) | 1.73 (1.24, 2.42) |
Previous non-diabetic hyperglycaemia | 1.59 (1.21, 2.09) | 1.18 (0.95, 1.46) | 1.76 (1.21, 2.56) | 1.19 (0.87, 1.61) |
Previous normoglycaemia | 2.05 (1.56, 2.70) | 1.47 (1.19, 1.83) | 2.20 (1.51, 3.20) | 1.35 (0.98, 1.85) |
Screening non-participants | 2.31 (1.82, 2.94) | 1.77 (1.47, 2.13) | 2.54 (1.82, 3.53) | 1.85 (1.44, 2.38) |
Among clinically detected individuals with diabetes who were screening participants, those who had had previous normoglycaemia tended to have higher rates of adverse health outcomes, with the exception of retinopathy, compared with those who had had previous OGTTs indicative of diabetes or non-diabetic hyperglycaemia (Table
3). In general, those who had had previous OGTT measurements in the diabetic range and those who had had previous non-diabetic hyperglycaemia had very similar HRs (e.g. all-cause mortality HR 1.61 and 1.59, respectively), whereas those who had had previous normoglycaemia had higher risks for all outcomes (e.g. all-cause mortality HR 2.05 [95% CI 1.56, 2.70]), with the exception of retinopathy (Table
4).
To explore whether some of the effect of mode of detection of diabetes among participants in screening could be explained by differences in an individual’s health status, we conducted sensitivity analyses adjusting for presence of a prior CVD event, and additionally for several biomarkers measured at previous screening (listed in Table
2), as well as time since previous screening (ESM Table
2). As a result, when adjusting for prior CVD event status, all estimates were attenuated but, with the exception of the HR of CVD events (HR 1.16 [95% CI 0.95, 1.41]), remained significant. Estimates were further attenuated when adjusting for additional biomarkers.
Unconfirmed screen-positive individuals were on average 1.7 years younger at the date of their diabetes-indicative OGTT screening result than those who had a confirmed diagnosis (Table
1); they had a higher mortality rate than for screen-detected diabetes, but a lower incidence rate for all other outcomes, and a very low incidence rate for renal disease and retinopathy (Table
3). Compared with confirmed screen-detected diabetes cases, unconfirmed screen-positive cases had higher risk of all-cause mortality (HR 1.35 [95% CI 1.01, 1.79]) but lower risk of CVD (HR 0.77 [95% CI 0.60, 0.98]) and substantially lower HR of renal disease (HR 0.41 [95% CI 0.25, 0.69]) and retinopathy (HR 0.08 [95% CI 0.04, 0.16]) (Table
4).
Discussion
In this study of a population included in an organised universal screening programme for diabetes, we found that a diagnosis of diabetes can be brought forward by an average of 4.6 years by screening asymptomatic individuals, and that screen-detected individuals appear to fare better than those with clinically detected diabetes after their diagnosis.
The lead time is somewhat longer than the 3.3 years and 2.2 years estimated in previous studies [
5,
7]. There are important differences with regards to screening interval and analytical approach between this study and the previous studies that may explain this difference. In the Ely cohort, one-third of the population was randomly invited to participate in screening for diabetes in 5 year intervals (screened population), and two-thirds of the cohort were not. However, at the third screening round, one-third of the population initially not included in the screening arm were randomly invited to take part (‘unscreened’ population). Lead time was calculated as the difference in median diabetes duration for the screened and ‘unscreened’ population, both of which included screen- and clinically detected individuals. In the ADDITION-Denmark study, high-risk individuals were invited to screening at one time-point, and lead time was calculated as the difference in median diabetes duration between screen-detected individuals vs. clinically detected individuals in the whole group eligible to be screened. In this study, we compared age at detection in individuals with screen-detected vs clinically detected diabetes who had been eligible to be screened in 10 year intervals.
We found that those with screen-detected diabetes had lower rates of all-cause mortality and incident CVD, renal disease and retinopathy than those with clinically detected diabetes. This is in line with the modelled estimated reduction in CVD events caused by earlier routine treatment that was found in a previous study [
24]. It is possible that the observed effect may be caused by the treatment that screen-detected individuals presumably received earlier than those whose diabetes had been clinically detected, but there are three important biases that may explain some of the effect.
The first is healthy user bias. Clinically detected individuals who were screening non-participants were detected on average 3.6 years earlier than clinically detected individuals who were screening participants, but despite being diagnosed with diabetes earlier, they had consistently worse health outcomes. On average, VIP non-participants had more than twice the rate of all-cause mortality than VIP participants when comparing age- and sex-standardised mortality rates. Similarly, it has been shown that in screening for human papilloma virus, regular non-attenders have about a twofold higher all-cause mortality than regular attenders [
25]. Although VIP is not a screening programme for diabetes, it is likely that the individual choice to attend the clinical examinations would be guided by similar behaviour to the choice to attend systematic organised screening programmes. In the VIP, participation has been linked to marital status and higher income, but not education [
12].
Second, there is length time bias. The idea that slowly developing disease with a longer asymptomatic preclinical screen-detectable course is also more likely to have a long clinical course and better prognosis [
26] has not previously been explored specifically for diabetes. However, our data indicate that this concept may be equally important for diabetes screening as it is for several cancers [
27]. It appears that slowly progressing hyperglycaemia and diabetes may be associated with better health outcomes than more rapidly progressing disease, as indicated by the fact that clinically detected individuals with diabetes who had normoglycaemia at their previous VIP examination had worse health outcomes after diagnosis than those who had been non-diabetic hyperglycaemic or who had had diabetes-indicative OGTT results. However, those who had diabetic or non-diabetic hyperglycaemia at their previous screening should have received lifestyle advice and referrals to continued care, which could have also contributed to a better prognosis after diagnosis. In addition, the mean time to diabetes detection from screening was about 4 years longer for those with previous normoglycaemia, and we cannot know for how long they would have lived with hyperglycaemia prior to their diagnosis. Ideally, we would have liked to test the contribution of length time bias by adjusting for health status and biomarkers for diabetes severity at the time of detection, but these data were not available. When we adjusted for several biomarkers associated with general health status measured at the previous screening, the estimates were attenuated, which supports a role of length time bias, but the analysis has limitations so a cautious interpretation is warranted.
The third source of bias is lead time bias. Although we adjusted for age at detection in the analyses, we cannot disregard the fact that there may be residual bias from differences in lead time as screen-detected individuals had on average a 1.5 years longer observation time owing to being detected earlier in the disease course than those with clinically detected diabetes [
28,
29].
Taken together, these data suggest that there may be a positive effect of early detection and treatment due to screening on survival and health outcomes after a diagnosis of diabetes, but how much is not within the scope of this study to determine. These results are in line with those from ADDITION-Denmark [
7].
We found that it was more common for a diabetes-indicative OGTT result to remain unconfirmed than to be confirmed within 1 year, which is in line with findings from previous studies [
8]. In this study, unconfirmed screen-positive individuals were overall younger and had consistently better health at the point of the positive diabetic screening result than confirmed screen-detected individuals with diabetes. They also had lower incidence rates of CVD and renal disease, a considerably lower incidence rate of retinopathy, but a higher mortality rate. There is reason to believe that some of the difference in retinopathy and renal disease rates is due to surveillance bias as individuals with confirmed diabetes are more likely to be tested for these conditions, but this is less likely to be the case for CVD events and is not the case for deaths. These results indicate that unconfirmed screen-positive individuals would potentially benefit from treatment for the management of blood glucose levels and related risk factors in order to reduce the risk of CVD [
30].
The primary strengths of this study were the large population size and the fact that we were able to study a model for an organised whole population-based screening programme for diabetes with follow-up for over 20 years that included participants as young as age 30 years. The main limitations were the relatively short follow-up period and that we could not assess the association between screening in general and health outcomes after diagnosis owing to the non-randomised design (lack of a non-screening control group). The diagnostic criteria for diabetes were revised during the study period when the fasting glucose level threshold in the OGTT was lowered from 7.8 mmol/l to 7.0 mmol/l in 1999 [
31], although it was unclear when this revision was implemented in the VIP, meaning that some individuals may have been misclassified. However, there were only ten screen-detected individuals (data not shown) within this range between 1992 and 1998, and since all diabetes cases in this group were confirmed by another source within 1 year, the resulting bias is likely to be limited. The median follow-up time was relatively short at 6.2–7.8 years, but the results were similar even after 10 years’ follow-up. We did not have access to data on marital status and income, variables that have been associated with propensity to participate in screening [
12], but we were able to control for SES. Individuals with clinically detected diabetes were identified from five different sources, and as a consequence systematic information on biomarkers associated with severity of diabetes at time of diagnosis was unavailable.
In conclusion, in this population-based study of screen- and clinically detected diabetes, we found that screen-detected individuals were detected at a younger age, and may have better survival and lower rates of CVD, renal disease and retinopathy than those who were clinically detected.