The impact of cancer on diabetes outcomes

Patients

The GPs included all of their patients who were 40 years or older and diagnosed with diabetes during the inclusion period. At a major laboratory, the diabetes diagnosis was confirmed by a single fasting whole blood/plasma glucose concentration (≥7.0/8.0 mmol/l). The protocol-based exclusion criteria were: unwillingness to participate, severe psychiatric disease or life-threatening somatic disease (Additional file 1: Figure S1). As previously reported, the randomization was balanced [16, 17]. In total 1369 (99.1%) of 1381 patients in the final study population were of Western European descent. Approximately 97.5% of the patients were classified as type 2 diabetes patients, which was based on the onset of insulin treatment. The Frederiksberg and Copenhagen Research Ethics Committee approved the study.

Intervention

The follow-up of patients in the intervention group consisted of examinations every three months and annual screening for diabetes complications. These examinations were facilitated by a questionnaire forwarded to the GP one month before the next expected consultation. The GP together with the patient was asked to define optimal goals for controlling important risk factors within three categories: ‘good,’ ‘acceptable,’ and ‘poor’ control. The emphasis was on glycemic control. At each quarterly consultation, GPs should compare the patient’s achievements with the goal and consider changing either goal or treatment accordingly. In overweight patients, the GP was prompted to agree with the patient on a small, realistic weight reduction, and this agreement should be recorded and followed up. However, participants were not required to target a particular body weight [16].

Through folders and leaflets for both physicians and patients, annual descriptive feedback reports on individual patients as well as six annual half-day seminars, GPs were introduced to possible solutions to therapeutic problems in the intervention group.

Generally, the importance of diet was stressed, and if possible, the GPs were recommended to postpone the start of glucose-lowering drugs until at least three months after diabetes diagnosis, to observe the effect of any weight loss. Further, the GPs were also prompted to recommend increased physical exercise and simple dietary rules [16, 17]. In cases of persistent hyperglycemia, metformin was recommended for patients who were overweight by clinical judgment. Glipizide or glibenclamide was suggested for patients of normal weight, and tolbutamide was recommended in patients older than 70 years. If the goal for blood glucose was not achieved and before starting insulin, a combination of metformin and a sulfonylurea was suggested as the last step. The preferred treatments for patients with hypertension were ACE-inhibitors or β-blockers; however, for patients with heart failure furosemide was preferred, and for patients older than 70 years thiazides were recommended. In cases of diet-resistant dyslipidemia, lipid-lowering drugs were recommended. To individualize the treatment, the GPs were allowed to deviate from the recommendations.

During the intervention phase, the GPs in the routine care group were free to choose any treatment and also to revise it [16]. The intervention was terminated on 26 September 1995, and the six-year examination was initiated. The study coordinators did not contact routine care practices during the intervention period after recruitment was completed and no attempt was made to maintain patients in randomized groups or to influence their therapy in the post-intervention period.

Clinical and registry-based follow-up

A description of all variables and definitions has previously been published [16–19]. After median (IQR) 5.57 (4.96–6.16) years in the structured personal care group and after 5.85 (5.30–6.45) years in the routine care group, a clinical follow-up examination was completed for 970 (93.4%) of 1039 surviving patients (Additional file 1: Figure S1).

Using the unique identification number assigned to all Danish residents in the Danish Civil Registration System, emigration and vital status of all patients were ascertained. This enabled unambiguous linkage between the study population and the Danish national registries [20]. On 31 December 2008, all surviving patients were censored. The Danish Register of Causes of Death supplied information about possible and underlying contributory causes of death [21]. In four patients, the cause of death was not recorded. Information on cancer diagnoses was obtained from The Danish Cancer Registry [22], however non-melanoma skin cancer and some ill-defined cancers were not included in our cancer diagnosis (Additional file 1: Table S1). The Danish National Patient Register gave information on contacts with hospitals in Denmark, e.g., surgical procedures performed and discharge diagnoses [23]. These registries provided information on the predefined outcomes: all-cause mortality, diabetes-related deaths, any diabetes-related endpoint, stroke, myocardial infarction, microvascular disease, and peripheral vascular disease [16] (Additional file 1: Table S2).

Statistical analysis

A description of the study design has also been reported earlier [16–18]. The incidence rates of the outcomes defined above were compared between structured care and routine care with hazard ratios (HRs) from Cox regression models on time from diagnosis to the first occurrence of the outcome; death and end of follow-up were censoring events. In these models, the accrual of a cancer diagnosis was modeled as a time-varying covariate. These comparisons were performed for patients with and without a cancer diagnosis separately to be able to assess whether there is a differential effect. Concurrently, in an auxiliary Cox regression analysis, the incidence rates for cancer were compared between structured care and routine care; these incidences are visualized in Kaplan-Meier curves. If a patient had an occurrence of an outcome before the diabetes diagnosis, this patient was excluded from the analyses about that outcome. In all assessments, we used a robust sandwich estimator to determine 95% CIs and P values to adjust for the clustering of patients within practices [24]. We further adjusted the comparisons for the following variables, assessed at diagnosis: sex, age, body mass index, hypertension, diagnostic fasting plasma glucose, total cholesterol, living alone, basic school education, sedentary physical activity, and current smoking. Incidence rates were calculated as the number of patients experiencing the corresponding outcome divided by the total person-time at risk. Patients with missing values in one or more variables were omitted from analyses where these variables were included.

Comparisons between structured care and routine care were done according to the intention-to-treat principle. Analyses were done using SAS (version 9.4). The level of statistical significance was 5%.

Strengths and limitations

The results from this post hoc analysis of a randomized controlled trial should be interpreted as observational, as the presence of cancer was not accounted for in the randomization procedure. In the period following a diabetes diagnosis, the enhanced medical examination could lead to increased detection of cancer, which has been reported in some studies [42] and rejected in another study [43]. However, in the present study, the intervention did not influence the detection of cancer (Fig. 1), as the rate of new cases of cancer did not differ between the two arms.

The distribution of types of cancers resulted in relatively small numbers of patients in different sub-classes of cancer (Additional file 1: Table S1), which prevented us from making subgroup analyses according to cancer type and stage. An observational study did not find any effect of tumor stage and site on diabetes quality indicators among cancer patients [38]. Nevertheless, it seems reasonable to assume that aggressive lung cancer or pancreatic cancer has a larger impact on the course of diabetes than limited skin cancers, which are not included in this study.

The group of patients who had cancer recorded before the diabetes diagnosis included only patients who had survived this cancer, and it did not include patients with terminal cancers as this was an explicit exclusion criterion. The group of patients who got a cancer diagnosis after the diabetes diagnosis did include more aggressive type of cancers. It is, therefore, a limitation of the present study that the effect of cancer was modeled without taking the timing of the cancer diagnosis into account. People who did not survive probably had more severe conditions and could have been treated less intensively as regards their diabetes and diabetic complications.

The cancer diagnoses were identified in the Danish Cancer Registry, which has been documented to have high completeness and accuracy [22, 44] (Additional file 1: Table S1).