This was a retrospective observational study (Fig. 1) conducted using US claims data from the Merative™ MarketScan® Commercial and Medicare Databases.
Fig. 1Study design. ASCVD atherosclerotic cardiovascular disease, CV cardiovascular, DPP4i dipeptidyl peptidase 4 inhibitor, GLP-1 RA glucagon-like peptide 1 receptor agonist, T2D type 2 diabetes
Individuals were included if they were at least 18 years old and had a claim indicating initiation of either semaglutide (injectable or orally administered) for T2D or a DPP4i during the index period (1 January 2018–30 September 2020). The index date was the date of treatment initiation. Eligible individuals required a diagnosis code for T2D on or at any time before the index date and at least 12 months’ continuous enrolment in the database pre-index (baseline period). For inclusion in the group with T2D and a history of ASCVD, individuals also required a diagnosis of ASCVD at any time pre-index, broadly defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM codes (online Supplementary Table S1). Individuals were followed from index date until the first stroke event (for the primary outcome analysis), end of enrolment in their insurance plan or the end of the study period (30 September 2020), whichever was earliest.
Individuals were excluded if they had a claim for orally administered or injectable semaglutide, any other GLP-1 RA, any DPP4i, an amylin analogue or insulin during the 12-month baseline period. Use of these medications on the index date was also an exclusion criterion, with the exception of treatment initiation with semaglutide or DPP4i on the index date in the corresponding study groups. Individuals with a diagnosis code for type 1 or secondary diabetes during the baseline period or on the index date or a claim associated with pregnancy or gestational diabetes at any time during the study period were also excluded.
Propensity Score Matching and Baseline CharacteristicsIndividuals were propensity score matched 1:1 using nearest neighbour matching without replacement, with a narrow width of calliper (0.1 rather than 0.2) to minimize the difference between matched pairs. For matching, iterations were performed by selecting multiple combinations of characteristics to obtain a balanced cohort. The final matching used 27 characteristics for the T2D groups and 26 characteristics for the T2D plus ASCVD groups (see online Supplementary Methods). Baseline demographic characteristics used in the matching (age, sex and region) were assessed at the index date. Baseline CV comorbidities were assessed using data from any time before the index date, whereas non-CV comorbidities, medication use and disease severity scores (Quan–Charlson Comorbidity Index and adapted Diabetes Complications Severity Index [aDCSI]) were assessed in the 12-month baseline period. The aDCSI has been shown to be a robust predictor of factors including hospitalizations, mortality and inpatient and prescription costs in claims data sets using ICD-9-CM [17] and ICD-10-CM [18] codes. After matching, the groups were considered to be well matched if the standardized mean difference was 10% or less.
OutcomesThe primary outcome was the time to first stroke event during follow-up, which was defined as a medical claim with stroke as the primary diagnosis (ICD-10-CM diagnosis codes I61 [nontraumatic intracerebral haemorrhage] and I63 [cerebral infarction]; online Supplementary Table S2) during an inpatient or emergency room visit; this could be either a primary or secondary stroke event. Individuals with no stroke event during follow-up were censored at the end of enrolment or the end of the study period, whichever was earliest.
HCRU during follow-up was included as a secondary outcome. The numbers of inpatient admissions, emergency room visits and outpatient appointments related to stroke were compared between the semaglutide and DPP4i groups. Numbers of visits are shown as per person per year (PPPY) × 1000. Two HCRU analyses were conducted: in the first, stroke was required to be present as the primary diagnosis; in the second, stroke could be either the primary or a secondary diagnosis.
The use of glucose-lowering medications during baseline compared with use during follow-up was also assessed. Individuals were considered to be using a glucose-lowering medication if they had at least one claim for the medication during the entire follow-up period (index date until end of enrolment in insurance or end of the study period, whichever was earliest). This analysis was intended to indicate how semaglutide or DPP4i initiation might affect receipt of other glucose-lowering medications, and to provide a broader context for the stroke events analysis by examining concomitant medication use.
Statistical AnalysesBaseline characteristics and medication use are reported using descriptive statistics. Numbers of stroke events, incidence rates (IRs) per 100 person-years and incidence rate ratios (IRRs) for semaglutide compared with DPP4i are reported.
Hazard ratios (HRs), 95% confidence intervals (CIs) and p values for stroke were calculated using a Cox proportional hazards model, with DPP4i as the reference group. Estimates were adjusted for baseline covariates (see online Supplementary Methods) to address any residual confounding. Adjusted mean rate ratios, 95% CIs and p values for HCRU were obtained via generalized linear models using a Tweedie distribution and log link function with number of visits as the dependent variable and treatment arm as a covariate. The estimates were adjusted for baseline characteristics. Variable follow-up time was adjusted for as an offset in the model. Unadjusted estimates for both analyses are also reported. p < 0.05 was the threshold for statistical significance.
Sensitivity AnalysesThree sensitivity analyses were conducted. In sensitivity analysis 1, only people who had not received an SGLT2i during the baseline period were included. In sensitivity analysis 2, to remove the possible confounding factor of recent stroke events, only people who had not had a stroke event (defined as in the main analysis) in the 90 days before the index date were included. In sensitivity analysis 3, individuals were censored upon discontinuation of semaglutide or DPP4i. Discontinuation was defined as a medication gap of at least 90 days, starting from the last day of treatment with the index drug. This date was estimated on the basis of the number of days’ supply on the last claim for index treatment. For the DPP4i groups, individuals were allowed to switch to a DPP4i other than the DPP4i received on the index date, and therefore a gap in the use of any DPP4i was considered as meeting this criterion.
Compliance with Ethics GuidelinesThis study was performed in accordance with the Declaration of Helsinki (1964). Ethical approval and informed consent were not required, because these were fully anonymized data. The data analysed during the study were licensed under an agreement between Novo Nordisk and Merative.
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