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Comparison of Cognitive Benefit Between SGLT-2 Inhibitors and Incretins

Dec 1, 2018
Editor: Joy Pape, MSN, FNP-C, CDE, WOCN, CFCN, FAADE

Author: Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy

Which antihyperglycemic agent will provide the greater cognitive benefit in patients who are elderly and have diabetes?

Recently, a correlation has been established between patients who are elderly and have  diabetes and an increased risk of developing cognitive impairment / dementia when compared to their counterparts who do not have diabetes. The effects of diabetes on cognitive decline as well as various methods to halt or reverse these effects have been a topic of interest for diabetes researchers. While the exact mechanism by which elevated glucose levels cause cognitive decline has not been elucidated, it has been shown that in patients who are elderly, there tends to be an inverse relationship between hemoglobin A1c and decline of cognitive function. Of the currently available antihyperglycemic agents available, the incretin-based medications, dipeptidyl peptidase 4 (DPP-4) inhibitors, and glucagon-like peptide type 1 (GLP-1) agonists have been shown to have a protective effect on cognitive function. The aim of this study is to compare the sodium-glucose (SGLT-2) inhibitors against incretin-based therapy to determine if SGLT-2 inhibitors elicit a similar preventive benefit.

A randomized controlled trial was selected for the study design as the researchers  wanted to determine causality of any observed benefit. Patients were considered for inclusion if they were greater than 65 years of age with diabetes and without any neurological disease, mental disorders, sensory impairment, or alcoholism. Patients were excluded if they had been diagnosed with dementia / mild cognitive impairment or were undergoing treatment with either non-steroidal anti-inflammatory or steroid medications. The primary outcome of the study was change in cognitive function from baseline. This was evaluated via the mini mental status examination (MMSE), a research-validated questionnaire for the evaluation of cognitive impairment. Secondarily, BMI / weight and metabolic laboratory values (lipids and glycemic values) were assessed. Both primary and secondary outcomes were assessed at baseline and then again at the end of the trial 12 months later. Once participants were eligible for inclusion, they were randomized into either the intervention group, which received an SGLT-2 inhibitor (canagliflozin 300mg per day, dapagliflozin 10mg per day, or empagliflozin 25mg per day), or the control group, which received an incretin-based medication (vildagliptin 100 mg per day, sitagliptin 100 mg per day, linagliptin 5 mg per day, or liraglutide at up to 1.8 mg per day). The data collected during the study was analyzed for significance via the one-way AVNOVA statistical test.

Of the 50 patients who were assessed, 39 were eligible and randomized into their respective groups. With the exception of total and LDL cholesterol, baseline characteristics between treatment groups were equivalent. At the close of the study, neither group showed any statistically significant change in average MMSE score when compared to baseline, indicating no cognitive decline in either group. Likewise, there was no significant difference between groups. With regards to the secondary outcomes, there was a statistically significant reduction in weight and BMI in the SGLT-2 inhibitor group compared to baseline (-1.95kg and -0.69kg/m2 respectively, p < 0.05 in both cases) where no significant difference was observed in the incretin group. Consequently, there was a statistically significant difference in BMI reduction from baseline between groups in favor of the SGLT-2 inhibitors.

The results of this study suggest that SGLT-2 inhibitors are non-inferior to incretin-based antihyperglycemic agents with regards to preventing cognitive decline in patients who are elderly and have diabetes.  The limitation of the study was the sample size was fairly small (39 participants in all with 18 and 21 in the control and intervention groups respectively) indicating that the study was likely underpowered. Also, the participants were in fairly good cognitive health, thus suggesting that 12 months may not be enough time for any sort of decline to take place. Despite its shortcomings, this study has an interesting premise and provides a foundation upon which further research should be conducted.

Practice Pearls:

  • Patients who are elderly and have diabetes and elevated A1C levels are at increased risk of cognitive decline / dementia when compared to their age-matched counterparts who don’t have diabetes.
  • Incretin-based antihyperglycemic agents have been previously proven to decrease the likelihood of cognitive decline in patients who are elderly and have diabetes.
  • SGLT-2 inhibitors may be as effective as incretin-based therapy in reducing risk of cognitive decline in patients who have diabetes; however, further research is needed in order to validate the findings of this study.


Perna, Simone, et al. “12-Month Effects of Incretins versus SGLT2-Inhibitors on Cognitive Performance and Metabolic Profile. A Randomized Clinical Trial in the Elderly with Type-2 Diabetes Mellitus.” Clinical Pharmacology: Advances and Applications, Volume 10, 2018, pp. 141–151., doi:10.2147/cpaa.s164785.

Rizzo, M. R., et al. “Dipeptidyl Peptidase-4 Inhibitors Have Protective Effect on Cognitive Impairment in Aged Diabetic Patients With Mild Cognitive Impairment.” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, vol. 69, no. 9, 2014, pp. 1122–1131., doi:10.1093/gerona/glu032.

Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy