Effect of screening for type 2 diabetes on risk of cardiovascular disease and mortality: a controlled trial among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009

The potential benefits of screening and early treatment for type 2 diabetes have been widely debated. Modelling studies suggest that screening might be both effective and cost-effective [1, 2, 3, 4, 5]. Screening and early treatment for diabetes appear to be associated with limited harms [6, 7]. Health check programmes including diabetes risk assessment have been proposed or introduced in a number of countries [8, 9]. However, trials of population-based screening for type 2 diabetes [10] and related cardiovascular risk factors [11] have failed to show significant overall benefit.

While the effect of screening at the population level might be smaller than expected, there may be benefits for those found to have diabetes. Results from the Anglo–Danish–Dutch Study of Intensive Treatment In People with Screen-Detected Diabetes in Primary Care (ADDITION)-Europe (ClinicalTrials.gov, number NCT00237549) showed that individuals diagnosed with diabetes and treated earlier had a risk of mortality that was similar to that reported for people of the same age without diabetes in the general population in Denmark [12]. One of the challenges of demonstrating potential benefit for those found to have diabetes following screening is that it would not be ethical to conduct a clinical trial of screening and early intervention compared with screening and delayed intervention [13]. As such, we cannot directly observe the magnitude of cardiovascular risk reduction that might occur among individuals with diabetes found by screening compared with those with no screening and hence no treatment until the time of clinical diagnosis [5]. Furthermore, simply comparing screen-detected individuals with clinically diagnosed individuals in a parallel cohort design tends to overestimate benefit because of lead and length time biases.

Between 2001 and 2006, a population-based cardiovascular risk assessment and diabetes screening programme was introduced in general practices in the Danish arm of the ADDITION-Europe study [14]. In the present study, using a controlled design, the Danish national registration system allows us to quantify the extent to which screening brings forward the diagnosis of diabetes, and to conduct a post hoc comparison of the risk of mortality and cardiovascular events among individuals with incident diabetes in the screening group and individuals with incident diabetes in the no-screening (control) group.

ADDITION-Europe is a cluster-randomised trial comparing the effects of screening for type 2 diabetes followed by intensive multifactorial therapy of individuals with screen-detected diabetes and screening followed by routine care [14, 15]. We report results from a post hoc analysis using data from the screening phase of the Danish arm of the study in conjunction with data from Danish national registers. Ethical approval for the ADDITION-Denmark study was granted by a local scientific committee (number 20000183). As this was a registry-based study using anonymised data, participants did not give informed consent. This approach was approved by the Danish Data Protection Agency and the Danish Health and Medicine Authority.

Sampling frame

We identified all eligible individuals in the original ADDITION-Denmark study (n = 153,107), including those who did not attend for screening, on the Danish National Registry system (the screening group). Using the same registry, we also identified all individuals aged 40–69 years without known diabetes who, between 2001 and 2006, were registered with general practices that were not invited to take part in ADDITION-Denmark or who declined to take part in ADDITION-Denmark (n = 1,759,285) (the no-screening control group). We then identified individuals from the screening and no-screening groups who were diagnosed with incident diabetes between 1 January 2001 and 31 December 2009 (Fig. 1). We included individuals diagnosed with diabetes during this period based on recent estimates of lead time, which suggest that there is around 3 years between detection by screening and clinical diagnosis. Including individuals diagnosed with diabetes in the 3 years (2006–2009) following the end of the ADDITION screening phase (2001–2006) would therefore capture most individuals in the no-screening group who could have been diagnosed by screening if they had been in the screening group. Our definition of incident diabetes for both groups was a proxy measure based on date of inclusion in the Danish National Diabetes Register [19]. We linked information about individuals diagnosed with diabetes to other Danish registers using unique civil registration numbers. We retrieved information on age, sex, education, immigration/emigration, citizenship, redeemed cardioprotective medication and chronic disease. Education was categorised according to Unesco’s International Standard Classification of Education [20]. We grouped data on citizenship into European and non-European as a proxy for ethnicity.

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Of 153,107 eligible people in the screening group, 27,177 (18%) attended their general practice for a diabetes test and cardiovascular risk assessment. Of these, 1533 participants (1% of those eligible for screening) were diagnosed with diabetes and agreed to take part in the study; 1406 of these were subsequently included on the diabetes register. There were 1,759,285 individuals in the no-screening group.

Median diabetes duration among clinically diagnosed individuals in the screening group was 6.6 years (interquartile range [IQR] 4.6 to 9.4) compared with 8.8 years (IQR 6.9 to 10.1) in screen-detected individuals in the screening group (difference 2.2 years, p < 0.001).

Median duration of follow-up was 6.2 years (IQR 4.2 to 8.8), with 898,285 person-years of observation. During follow-up, there were 1775 deaths in people with diabetes in the screening group (12.7%) and 19,739 deaths in people with diabetes in the no-screening group (15.8%) (Table 3). The HR for mortality was 0.79, 95% CI 0.74, 0.84, p < 0.0001 (Fig. 2). The most common cause of death was cancer (n = 10,500; 38.2%). In sub-group analyses, the HR for mortality was similar among individuals aged <55 years and ≥55 years (HR 0.81, 95% CI 0.71, 0.93, and HR 0.78, 95% CI 0.73, 0.84, respectively). The HRs for mortality were 0.82 (95% CI 0.76, 0.88) in men and 0.75 (95% CI 0.68, 0.82) in women.

Table 3

Incidence of all-cause, cardiovascular-, cancer- and diabetes-related mortality, and CVD events, in individuals with diabetes, by screening group (2001 to 2012)

Variable	Screening group (n = 13,992)			No-screening group (n = 125,083)			Crude HR (95% CI)	Adjusted HRa (95% CI)
	Number of events	Person-years follow-up	Rate per 1000 person-years (95% CI)	Number of events	Person-years follow-up	Rate per 1000 person-years (95% CI)
All-cause mortality	1775	97,265	18.2 (17.4, 19.1)	19,739	801,019	24.6 (24.3, 25.0)	0.71 (0.68, 0.75)	0.79 (0.74, 0.84)
Cardiovascular mortality	509	97,265	5.2 (4.8, 5.7)	5835	801,019	7.3 (7.1, 7.5)	0.70 (0.64, 0.77)	0.80 (0.72, 0.88)
Cancer mortality	954	97,265	9.8 (9.2, 10.5)	9546	801,019	11.9 (11.7, 12.2)	0.79 (0.74, 0.84)	0.83 (0.77, 0.89)
Diabetes-related mortality	121	97,265	1.2 (1.0, 1.5)	1701	801,019	2.1 (2.0, 2.2)	0.57 (0.48, 0.69)	0.66 (0.54, 0.81)
Composite cardiovascular event (first of CVD death, non-fatal IHD or non-fatal stroke)	2854	86,317	33.1 (31.9, 34.3)	28,487	698,893	40.8 (40.3, 41.2)	0.78 (0.75, 0.81)	0.84 (0.80, 0.89)

^aHRs were estimated with a Cox proportional hazards regression model. Robust standard errors were calculated that take into account the two-level structure of the data and any potential correlation between individuals within practices

Models were adjusted for age, sex, education and prevalent chronic disease (IHD, stroke, cancer); baseline hazards were stratified by county

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Cardiovascular mortality and cancer mortality were both significantly lower in the screening group compared with the no-screening group (HR 0.80, 95% CI 0.72, 0.88 and HR 0.83, 95% CI 0.77, 0.89, respectively). Diabetes was listed anywhere on the death certificate in 1822 individuals (121 in the screening group and 1701 in no-screening group), with a significant difference between groups in diabetes-related mortality (HR 0.66, 95% CI 0.54, 0.81).

There were 2854 first CVD events among people with diabetes in the screening group (20.4%) and 28,487 first CVD events among people with diabetes in the no-screening group (22.8%) (Table 3), with a significant difference between groups (HR 0.84, 95% CI 0.80, 0.89) (Fig. 3).

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In this very large population-based sample of middle-aged Danish adults with 898,285 person-years of follow-up, a single round of diabetes screening and cardiovascular risk assessment was associated with a 21% reduction in all-cause mortality rate and a 16% reduction in CVD events between 2001 and 2012 in individuals diagnosed with diabetes between 2001 and 2009. Individuals with clinically diagnosed diabetes were identified on average 2.2 years later than individuals with diabetes detected by screening.

One argument for considering screening for type 2 diabetes is the historical observation [22] that there is an extended latent or pre-clinical phase (lead time) in which people could be diagnosed and during which earlier treatment might have a beneficial long-term effect. More recently, changes in clinical practice with greater testing and public awareness have probably led to a shortening of this latent period. Data from the parallel-group population-based Ely study suggested that the lead time is relatively short at 3.3 years [23]. This is comparable with our more contemporary estimate of 2.2 years. However, the lead time may be longer in less developed health systems and/or in more deprived populations. In addition, the historical estimate of 9 to 12 years by Harris et al. [22] and the more recent estimate of 6 years from Porta et al. [24] relates to the true point of onset of diabetes. This is not the same as the point at which diabetes is detectable by screening, especially if screening is infrequent and not 100% sensitive. The period between true onset and clinical diagnosis of diabetes may be long precisely because there are few clinical manifestations during this period [23].

Even with a relatively modest lead time, our screening programme was associated with a significant reduction in mortality and incident CVD in individuals with diabetes over 6 years of follow-up. As only 10.1% of individuals in the screening group were actually diagnosed by screening, it is likely that the programme had wider effects in this cohort e.g. by delaying diagnosis and providing lifestyle advice (and perhaps treatment) among those screened and found to be at risk who were later diagnosed clinically. The difference in mortality and CVD might also have been driven by screening practices that were vigilant for diabetes even after the programme had finished, contributing to continued earlier detection and the higher diabetes incidence observed in screening compared with no-screening practices.

Our findings support results from modelling studies showing that screening programmes could contribute to a reduction in risk of mortality and cardiovascular morbidity in screen-detected individuals [1, 2, 3, 4, 5]. Herman et al. used a validated computer simulation model in ADDITION-Europe to show that screening and routine care, compared with a 3 year delay in diagnosis and routine care, was associated with a 17% relative risk reduction in all-cause mortality after 5 years [5]. They argue that the benefits of screening and treatment primarily accrue from early diagnosis and by hastening the treatment of CVD risk factors in the lead time [5]. We observed a rapid increase in the proportion of screen-detected individuals who redeemed cardioprotective medication during follow-up. However, larger proportions of clinically diagnosed individuals in the no-screening group redeemed medication compared with clinically diagnosed individuals in the screening group. As individuals in the no-screening group were diagnosed at a later stage in the disease trajectory, they may have had higher cholesterol, blood glucose and blood pressure values at diagnosis compared with the screening group, necessitating higher levels of cardioprotective medication. It is likely that promotion of healthy behaviour change also impacted on CVD and mortality rates in the screening group. Those who attended screening reported their smoking status at baseline (28%), which was similar to national self-reported smoking prevalence data in 2004 (Danish National Health Service survey) [25]. One-third of screen-detected individuals in ADDITION-Denmark reported that they had stopped smoking at 5 year follow-up. Furthermore, this cohort lost an average of 2 kg in weight [12]. If similar behavioural responses were observed among other individuals diagnosed with diabetes in the screening group, this suggests potential mechanisms for the risk reduction observed other than prescribed treatment. We also observed lower rates of cancer incidence in the screening group, which might be linked to changes in health behaviour and prescribing [26].

In a separate paper [11], we examine the impact of the ADDITION-Denmark screening programme at the population level, e.g. comparing all individuals aged 40 to 69 years in the screening and no-screening groups, and showed no long-term reduction in mortality or CVD. As such, our results mirror those from trials of screening for other conditions, which have shown reductions in disease-specific mortality but not in overall mortality [27]. There appeared to be beneficial effects for all those diagnosed with diabetes in the screening practices, regardless of the mode of diagnosis e.g. by screen detection or by clinical diagnosis. However, this benefit is too small to impact on overall population risk of CVD events and mortality [10, 11].