ADDITION-Denmark consists of two phases: (1) a stepwise screening programme; and (2) a cluster-randomised parallel-group trial comparing the effects of intensive multifactorial treatment with routine care among individuals with screen-detected type 2 diabetes [1, 2]. In brief, between 2001 and 2006, we performed a population-based stepwise screening programme among people aged 40–69 years without known diabetes in 175 general practices in Denmark. Eligible individuals were sent a diabetes risk score questionnaire [3] with an invitation to visit their family doctor for a diabetes test and a cardiovascular risk assessment (heart SCORE) [4] if they scored ≥ 5 points (maximum 15 points) on the risk questionnaire. The diabetes risk score questionnaire estimates diabetes risk using age, sex, BMI, known hypertension, leisure time physical activity and family history of diabetes [3]. The heart SCORE estimates fatal CVD risk using age, sex, smoking, systolic blood pressure and total cholesterol [4]. Participants who attended a screening appointment underwent measurement of height, weight, blood pressure, random blood glucose (RBG), total cholesterol and HbA1c. Individuals with an RBG ≥ 5.5 mmol/l or HbA1c ≥ 5.8% (40 mmol/mol) were invited to return to the practice for further testing. The WHO 1999 criteria, based on a standard OGTT, were used to diagnose diabetes [5]. Participants diagnosed with type 2 diabetes were subsequently managed according to the treatment regimen to which their practice had been allocated: routine care (control) or intensive treatment. Ethical approval for the trial was granted by the Region Midt Ethical Committee, Denmark. 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.
For those diagnosed with diabetes, general practitioners and nurses received training and support in delivering intensive treatment via small group or practice-based educational meetings where treatment targets/algorithms, lifestyle advice and supporting evidence were discussed [2]. Intensive treatment practices received additional funding to support the delivery of care, which included target-driven management of hyperglycaemia and blood pressure and cholesterol levels by medical treatment and promotion of healthy lifestyles, based on the stepwise regimen used in the Steno-2 study and other trial results. In the routine care (control) group, general practitioners were advised to follow Danish national recommendations for diabetes treatment and received no further follow-up. In both groups, practitioners were encouraged to treat normoglycaemic individuals with a heart SCORE ≥ 5, according to Danish guidelines [6].
In this secondary analysis, in order to assess the potential spillover effect of the intervention, we identified individuals who underwent screening as part of ADDITION-Denmark and who were normoglycaemic on biochemical testing. Normoglycaemia in our study refers to individuals with an RBG < 5.5 mmol/l and HbA1c ≤ 6% (42 mmol/mol) at the first visit/blood test, and people with fasting blood glucose < 5.6 mmol/l and 2 h blood glucose following an OGTT < 7.8 mmol/l. Participants were followed for a median of 8.9 years to 31 December 2011, when national registers were searched for information on vital status and a composite of first event of cardiovascular death (ICD-10 codes I60 to I69, I20 to I25, and I46), non-fatal ischaemic heart disease (ICD-10 codes I20 to I25, and I46) or non-fatal stroke (ICD-10 code I60 to I69).
Statistical analysis
Characteristics were summarised separately in the intensive treatment and routine care (control) groups. Date of entry to the study was set as date of invitation to screening. Individuals were censored on the date of first event following invitation for screening (for the incident CVD analysis), upon death, or on the 31 December 2011 (final date of follow-up), depending on which occurred earliest. HRs comparing incident CVD events and all-cause mortality between the groups were estimated with a Cox proportional hazards regression model and we accounted for clustering at the general practitioner level. We tested the proportional hazards assumption by including a variable for treatment by time interaction in the Cox regression model (p > 0.05). We also examined these associations in all individuals with a heart SCORE of ≥ 0 to < 5, ≥5 to <10, and ≥ 10. All analyses were completed using Stata Version 14.1 (StataCorp, College Station, TX, USA).