Comparative effectiveness of glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes in Sweden: an emulated trial study

Abstract

Background: The comparative effectiveness of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes mellitus (T2DM) is unknown.

Methods: We conducted a sequential trial emulation from 1st January 2010 to 30th June 2020 using data from Swedish national registers. Swedish residents who were aged 65 or older, had type 2 diabetes (T2DM), and initiated GLP-1 agonists, DPP-4 inhibitors, or sulfonylureas were followed for up to 10 years to assess the risk of dementia. Participants who had dementia, used the three drug classes, or had contraindications were excluded from enrollment. The characteristics between arms were balanced through the application of propensity scores estimated from predefined covariates. Intention-to-treat effects were analysed with all enrolled participants, while the per-protocol effects were analysed with participants who adhered to the assigned treatment.

Findings: The pooled trial included 88,381 participants who received prescriptions for GLP-1 agonists (n = 12,351), DPP-4 inhibitors (n = 43,850), or sulfonylureas (n = 32,216) at baseline and were followed for an average of 4.3 years. A total of 4607 dementia cases developed during follow-up: 278 for the GLP-1 agonist initiators (incidence rate: 6.7 per 1000 person years), 1849 for DPP-4 inhibitor initiators (IR: 11.8), and 2480 for sulfonylurea initiators (IR: 13.7). In an intention-to-treat analysis, GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60-0.79, p < 0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68-0.88, p < 0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses. These findings were consistent in several sensitivity analyses, including a per-protocol analysis (HR for sulfonylureas: 0.41, 95% CI: 0.32-0.53, p < 0.0001; HR for DPP-4 inhibitors: 0.38, 95% CI: 0.30-0.49, p < 0.0001).

Interpretation: Our research suggested that GLP-1 agonists were associated with a lower risk of dementia compared to sulfonylureas and DPP-4 inhibitors in older individuals with T2DM. Further clinical trials are needed to validate these findings.

Funding: Swedish Research Council, Karolinska Institutet, the National Institute on Aging, the National Institutes of Health, and Riksbankens Jubileumsfond.

Keywords: Antidiabetic drugs; Dementia; Emulated trial study.

Fig. 1

Sequential trial emulation design and inclusion of participants. a) Timeline of sequential trial emulation from January 2010 to June 2020. b) Inclusion and exclusion of participants for the pooled emulated trials. To maximize the sample size, we conducted a monthly sequential trial emulation from January 2010 to June 2020. Participants were treated as independent individuals each month. Those who met the eligibility criteria were included in the trial. To avoid bias resulting from varying look-back periods, we used a consistent look-back period of 5 years for the inclusion criteria in each trial. The numbers presented for the inclusion and exclusion of participants include repeated individuals, since participants meeting the eligibility criteria multiple times in the sequential trial emulation were enrolled in this study repeatedly. T2DM indicates type 2 diabetes mellitus. GLP-1 agonists, glucagon-like peptide-1 agonists. DPP-4 inhibitors, dipeptidyl peptidase 4 inhibitors.

Fig. 2

Weighted cumulative hazard for incident dementia in GLP-1 agonist, DPP-4 inhibitor, and sulfonylurea groups. a) Weighted cumulative hazard for dementia from intention-to-treat analysis. b) Weighted cumulative hazard for dementia from per-protocol analysis. The analysis included a total of 12,351 initiators of GLP-1 agonists, 43,850 initiators of DPP-4 inhibitors, and 32,216 initiators of sulfonylureas. For the per-protocol analysis, the adherence rates were 30% in the GLP-1 agonist group, 40% in the DPP-4 inhibitor group, and 16% in the sulfonylurea group. Intention-to-treat analysis was adjusted for the predefined baseline covariates, while per-protocol analysis further considered adherence to the assigned treatment with adjustment for the predefined baseline covariates and time-varying covariates along follow-up. GLP-1 agonists are glucagon-like peptide-1 agonists. DPP-4 inhibitors are dipeptidyl peptidase 4 inhibitors. Light-colored bands represent the 95% confidence interval for each treatment.

Fig. 3

Weighted hazard ratios for dementia for pairwise comparisons between GLP-1 agonist, DPP-4 inhibitor, and sulfonylurea groups for both intention-to-treat and per-protocol effects. This figure illustrates weighted hazard ratios for dementia, as derived from both intention-to-treat (upper panel) and per-protocol analyses (lower panel). Pairwise comparisons were conducted using the latter drug as the reference. The intention-to-treat analysis of overall participants considered a five-year look-back period for eligibility assessment. Analyses of look-back to 2004 utilized an as-available look-back period to 2004 in our cohort. In the liraglutide analysis, only participants initiated on liraglutide were included in the GLP-1 agonist group, and the estimates for the comparison of liraglutide to DPP-4 inhibitors and sulfonylureas were provided. To account for possible register lag time in dementia diagnoses, analyses with lag times of 1, 3, and 5 years were conducted. Participants receiving a dementia diagnosis within 1, 3, or 5 years from baseline were censored accordingly. Additional analyses focused on specific subgroups by sex (men and women) and age (65–75 and ≥75 years old). The analysis concerning T2DM diagnosis in the past 5 years only included participants with T2DM records in the National Patient Register for the five years prior to baseline. The analysis with washout since 2009 extended the washout period to 2009 for an analysis that only considers the first initiation of the investigated treatments from 2010 to 2020 (no reuses of participants in sequential trial emulation). The analysis of excluding cerebrovascular diseases excluded the participants diagnosed with cerebrovascular diseases within the five years prior to baseline. The analysis of metformin only users only included the participants who exclusively received dispensation of metformin monotherapy in the preceding year to baseline, while the analysis of insulin users included the participants who ever used insulin within the year before baseline and had been performed only for comparison between GLP-1 agonists and DPP-4 inhibitors. All intention-to-treat analyses were adjusted for the predefined baseline covariates, while per-protocol analysis further considered adherence to the assigned treatment with adjustment for the predefined baseline covariates and time-varying covariates along follow-up. 'Not applicable' indicates the corresponding analysis was not feasible or necessary due to certain considerations. GLP-1 agonists refer to glucagon-like peptide-1 agonists. DPP-4 inhibitors are dipeptidyl peptidase 4 inhibitors.