Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case–control study

Abstract

Objective Diabetes is a risk factor for dementia, but whether antidiabetic medication decreases the risk is unclear. We examined the association between antidiabetic medication and dementia. Design We performed a nested case–control study within a cohort of all 176 250 patients registered with type 2 diabetes in the Danish National Diabetes Register between 1995 and 2012. This population was followed for dementia diagnosis or anti-dementia medication use until May 2018. Using risk-set sampling, each dementia case (n = 11 619) was matched on follow-up time and calender year of dementia with four controls randomly selected among cohort members without dementia (n = 46 476). Ever use and mean daily defined dose of antidiabetic medication was categorized in types (insulin, metformin, sulfonylurea and glinides combined, glitazone, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose). Methods Conditional logistic regression models were fitted to calculate odds ratios (ORs) for dementia associated with antidiabetic medication use, adjusting for potential confounders. Results Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower odds of dementia after multible adjustments (ORs of 0.94 (95% confidence interval (CI): 0.89–0.99), 0.80 (95% CI 0.74–0.88), 0.58 (95% CI: 0.50–0.67), and 0.58 (95% CI: 0.42–0.81), respectively), with a gradual decrease in odds of dementia for each increase in daily defined dose. Analyses of the most frequent treatment regimes did not show any synergistic effects of combined treatment. Conclusion Use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors was associated with lower risk of dementia in patients with diabetes.

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan

“…Our results demonstrated that the types of DPP-4i had a class effect on dementia prevention, with a main focus on vascular dementia, but not on AD. These results were not consistent with those of previous human studies [21,22,26]. The discrepancy among the studies may be attributed to the populations and numbers of the study participants, study designs, durations of follow up, and end points of the studies (cognition and dementia definitions and types).…”

“…The latest nested case control study from a cohort of 176,250 patients registered in the Danish National Diabetes Register study showed that the use of DPP-4i in T2D patients significantly decreased the risk of dementia compared to in non-DPP-4i users during a long duration of follow up (7.2 years). However, this study did not reveal the effect of DPP-4i on different types of dementia [26].…”

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status

“…12 The DPP4 inhibitors can affect systems unrelated to GLP1, 26 and therefore further studies would be needed to understand the mechanism(s) of action relevant to memory, and to determine whether the GLP1 receptor agonists (incretins) would be equally beneficial. 32 We did not assess relationships between insulin use and memory because insulin is likely to reflect longer duration of diabetes, resulting in a considerably different propensity to receive insulin therapy leading to confounding by indication. Instead, insulin use was controlled for in the analyses.…”

Benefit Class of Second-line Anti-diabetic Medication on Types of Dementia in Type 2 Diabetes: A Nationwide Real-world Longitudinal Study

“…DPP-4i increases the glucose-dependent insulin response and reduces glucagon secretion by inhibiting GLP-1 degradation [28]. Wium-Andersen, et al showed DPP-4i ever-users had a lower odds of dementia than never-users (OR= 0.80, 95% CI 0.74-0.88) and the Met + DPP-4i dual combination was associated with a lower odds of dementia than no anti-diabetes medication (OR = 0.70, 95% CI 0.58-0.86) [20]. In subclasses of dementia, Kim, et al demonstrated that DPP-4i new users versus SU new users over 60 years old had a lower risk of all-cause dementia and AD (HR = 0.66, 95% CI 0.56-0.78 and HR = 0.64, 95% CI = 0.52-0.79), but not VaD (HR = 0.56, 95% CI 0.38-1.14) over 4 years [14].…”

“…In combination with Met, Lu et al reported that 204,323 Taiwan patients with T2D and ≥ 65 years that MET + TZD was signi cantly superior to Met + SU in the risk of developing dementia (HR = 0.56) [15]. On the other hand, a nationwide nested case-control study, enrolled from 1995 to 2012, reported that TZD ever-users, including rosiglitazone, versus never-users did not have a signi cant odds of developing dementia (OR = 0.89, 95% CI 0.76-1.03), but further analysis of dual therapy with TZD was not conducted [20]. In Korea, there are two TZDs, lobeglitazone and pioglitazone, approved by the Ministry of Food and Drug Safety.…”