Study Design
The main objective of the study was to compare the incidence of the defined and confirmed microvascular event outcomes following exposure to one of two therapies: vildagliptin and sulfonylurea. To achieve this objective, a retrospective cohort study design was used in which exposure, outcome, and possible confounding variables were measureable. Since the source of data was longitudinal electronic medical record (EMR), the cohorts were defined by diagnoses and exposures recorded historically, with outcomes tracked over the course of the study period. As such, there was no need for patient informed consent and ethical committee approval according to the German and European law.
Settings
Patients’ data was extracted from IMS Lifelink EMR Disease Analyzer (DA), Germany. This database captures data from German patients who visit a representative panel of physicians composed of both general practitioners and specialists. The panel was constituted through stratified sampling of physicians at national level with annual turn-over of 10–20% of the sample. The records of patients who visit the panel were de-identified and sent to a central EMR database in IMS Health. The content of the patient records was then coded through the appropriate coding systems [Anatomical Therapeutic Chemical (ATC) Classification System for drugs and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) for diagnoses]. The information of the database is updated monthly. Due to non-interventional nature of the present study, it did not impose a therapy protocol, diagnostic/therapeutic procedure, or a visit schedule. The analyzed data was from the period of January 2007 to December 2013.
Participants
Participants were patients with T2DM treated in an outpatient care as per recorded in IMS Lifelink EMR DA Germany database in the defined study period. Inclusion criteria included having a record of diagnosis of T2DM before or at the time of inclusion (as defined by ICD-10 code E11), treatment initiation by either vildagliptin or sulfonylurea, at least 6 months of continuous treatment (the index date was the date of initiation on therapy), continuous available follow-up in the database as defined by at least one visit every 6 months, and aged greater than 40 years.
The exclusion criteria included a recorded history of microvascular complications before treatment by one of the above medications and concurrent treatment by both vildagliptin and sulfonylurea.
History of each microvascular complication was considered as an exclusion criterion for when it was analyzed as the outcome. The exclusion criterion of previous microvascular event was applied separately for each type of event. For example, for the outcome of retinopathy, patients were selected for the analysis if they had no previous record of retinopathy, and for the outcome of nephropathy, patients were selected if they had no previous history of nephropathy. Hence, patients excluded from the analysis of one outcome may be included in the analysis of a different outcome. For the combined outcome, patients were excluded if they have a record of any previous event.
To avoid confounding between comparison groups of vildagliptin vs. sulfonylurea, matched samples were created using propensity score matching (see “Statistical Analysis” subsection for details).
Outcomes
The primary endpoint was defined as the first recorded occurrence of diabetic nephropathy (ICD-10 codes: E11.2, E14.2), diabetic retinopathy (ICD-10 codes: E11.3, E14.3), diabetic neuropathy (ICD-10 codes: E11.4, 14.4), and diabetic foot syndrome (DFS; through natural language processing, as there is no ICD-10 code for this pathology).
In addition, a combined endpoint of first recorded occurrence of nephropathy, retinopathy, neuropathy, or DFS was computed. The secondary endpoint was the time from initiation of therapy to the first occurrence of either nephropathy, retinopathy, neuropathy, or DFS. DFS was identified through textual analysis of the physicians’ notes which captured associated events, such as amputation, gangrene, etc.
Statistical Analysis
Descriptive statistics were calculated for all study variables and consist of number and percentage for categorical variables, as well as mean, median, minimum, maximum, and standard deviation for continuous variables with 95% confidence interval (CI).
The primary outcomes, as defined above, were assessed by unadjusted and adjusted odds ratios (ORs; with 95% CI), expressing the difference in risk of microvascular events (individual and combined) for patients prescribed vildagliptin or sulfonylurea. CIs were estimated using the Miettinen–Nurminen method. Secondary outcomes (time-to-microvascular event) were analyzed using Kaplan–Meier survival curves and the log-rank test. Incident rate ratios (IRR) were also calculated for different microvascular complications comparing two treatment groups (vildagliptin vs. sulfonylurea).
To account for potential confounding factors between two study groups (vildagliptin vs. sulfonylurea), matched samples were created using propensity score matching, i.e., the vildagliptin and sulfonylurea groups were selected to have similar profiles of propensity scores. The propensity scores were derived from the probability of treatment assignment conditional on the following confounding factors (covariates): age, sex, line of therapy, HbA1c score, duration of disease (<5 years vs. ≥5 years), duration of treatment, previous hypoglycemic events, co-prescribed medications, and number of co-morbidities. These confounding factors could act as potential sources of bias in evaluating main objectives of the study, and hence, patients with similar demographic and clinical characteristics in two study groups (matched samples) were pooled. Propensity score-based matching criteria with respect to various confounding factors were used to derive matched samples between two study groups. Propensity scores were generated using a logistic regression model and matched using a genetic algorithm for closest matching based on propensity scores and covariate balance. The distribution of propensity scores and covariates was examined by group to allow for the degree of matching to be quantified (see Fig. 1).
A preliminary feasibility study was conducted to determine the sample size. Based on the data collected for the feasibility study, we estimated the frequency of microvascular complications (combined endpoint) for patients prescribed sulfonylurea as 11.9%, with a reduction of 4.1% for patients prescribed vildagliptin, and hence, the revised sample size requirement for the main study was 3144 patients for 95% power at the 0.01 significance level. All calculations were performed using R 3.0.2.