SGLT-2 Inhibitors Reduce Dementia Risk vs DPP-4 Inhibitors

Patients with type 2 diabetes treated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have a significantly lower risk of developing dementia and Alzheimer’s disease than those receiving dipeptidyl peptidase-4 (DPP-4) inhibitors, with the benefits appearing to increase over time, findings from a large population-based study showed.

“SGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment,” concluded the authors of the study, which was published this month in The BMJ. However, they also cautioned that the observational results are subject to limitations and require confirmation in randomized controlled trials.

The risk for dementia with type 2 diabetes has been shown to be increased by as much as 60%, with those individuals predisposed to both Alzheimer’s disease and vascular dementia.

Key factors linked to the risk include insulin resistance, hypoglycemic episodes, and vascular compromise, the authors noted.

Measuring the SGLT-2 Impact

With previous research showing treatment with SGLT-2 inhibitors was associated with a greater reduction in the risk for dementia than DPP-4 treatment among people older than 66 years with type 2 diabetes, the researchers sought to further evaluate the risk in a broader age range of patients and in more specific dementia types.

They used propensity score matching in a 1:1 ratio to identify 110,885 matched pairs of new users of SGLT-2 inhibitors or DPP-4 inhibitors in the Korean National Health Insurance Service database.

The patients (mean age, 61.9 years; range, 40-69 years; 55.7% men) were free of known dementia at baseline. They were matched based on factors such as psychiatric disorders, cardiovascular disease, other comorbidities, and the use of drugs with anticholinergic activity.

Overall, patients had a mean comorbidity score of 2.4. Most patients had hypertension (66.5%) and/or hyperlipidemia (78.6%).

The most common oral antiglycemic agents used during the baseline period were biguanide (52.2%), followed by sulfonylurea (27.8%) and thiazolidinedione (8.2%).

The most common index SGLT-2 inhibitor was dapagliflozin (58.6%), followed by empagliflozin (35.4%), whereas the most common index DPP-4 inhibitors were gemigliptin (22.7%), linagliptin (22.4%), and sitagliptin (20.4%).

With a mean follow-up of 670 days, 1172 patients were diagnosed with new-onset dementia, with incidence rates per 100 person years lower among those who initiated SGLT-2 vs DPP-4 inhibitors (0.22 vs 0.35, respectively).

In stratifying by types of dementia, those initiating SGLT-2 inhibitors had significantly lower rates of developing dementia (hazard ratio [HR], 0.65), dementia requiring drugs (HR, 0.54), Alzheimer’s disease (HR, 0.61), and vascular dementia (HR, 0.48) than those initiating DPP-4 inhibitors.

Similar outcomes were observed in an intention-to-treat analysis and across various subgroups, which were stratified by age, sex, concurrent metformin use, and baseline cardiovascular risk.

Of note, the risk for dementia declined further with treatment for more than 2 years (HR, 0.52) vs less than 2 years (HR, 0.57).

In other outcomes, those treated with SGLT-2 inhibitors vs DPP-4 inhibitors had a significantly higher risk of developing genital infections (HR, 2.67), whereas the risks for osteoarthritis-related encounters and cataract surgery were slightly lower (HR, 0.97 and 0.92, respectively).

“This large population-based cohort study among adults aged 40-69 years with type 2 diabetes found a 35% reduced risk for dementia associated with use of SGLT-2 inhibitors compared with DPP-4 inhibitors,” the authors concluded.

Possible Mechanisms Behind the Effect

Senior author Eun Ha Kang, of the Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea, speculated on potential mechanisms that could provide the neuroprotective effects.

“Many animal studies have shown the neuroprotective effects of SGLT-2 inhibitors, such as inhibition of acetylcholinesterase, prevention of beta-amyloid deposition, restoration of mTOR pathway, etc, but these effects were neither directly proven in humans nor head-to-head compared with DPP-4 inhibitors,” Kang told Medscape Medical News.

However, “since our study is observational rather than experimental, we do not prove a causal relationship, but only provide a strong basis for a future randomized controlled trial.”

Nevertheless, “since the success rate of drug development for dementia is extremely low, we should focus on modifiable risk factors, including diabetes and antidiabetic drugs,” Kang said.

Commenting on the findings in accompanying press materials provided to the Science Media Centre, Ivan Koychev, PhD, a senior clinical researcher at Dementias Platform UK, University of Oxford, Oxford, England, agreed that the mechanisms of SGLT-2 inhibitor effects on dementia risk, “likely relate to either affecting inflammation in the brain, reducing the risk for cerebrovascular events, or modulating glucose metabolism in the brain.”

“The caveat, as in previous epidemiological studies, is that it is not possible to draw causal links from such study designs. However, they strengthen the case for testing in clinical trial settings these types of drugs in people at risk for dementia.”

Repurposing an Established Drug to Treat Dementia 

Despite these limitations, it was agreed that the study carried important potential benefits in that its results were obtained with a drug already in common use.

“The great advantage of this so-called repurposing approach (ie, using an existing drug in a new indication) is that it reduces greatly the risk of the drug failing through safety concerns as they are already used in everyday clinical practice,” Koychev noted.

Jacqui Hanley, head of research at Alzheimer’s Research UK, Cambridge, England, agreed that repurposing drugs may be key in tackling dementia and Alzheimer’s disease.

“Roughly a third of drugs in clinical trials for Alzheimer’s disease are already used for other conditions,” said Hanley, also commenting through the Science Media Centre.

“If we are to cure dementia, clinicians will need a tool kit of treatments which tackle different aspects of the disease and can be used in combination. Research into repurposing drugs may help us do just that.”

The study was supported by the Korea Health Industry Development Institute-AZ Diabetes Research program. Koychev has received a grant to conduct a study of semaglutide in dementia and speaker fees from Novo Nordisk. He is a paid medical advisor for digital healthcare (Five Lives SAS, Cognes, Cognetivity, Lola Speak) and biotechnology (CFDX Ltd) companies in the dementia space. Hanley had no disclosures to report.