Differences in effectiveness among antihyperglycemic drugs on dementia risk identified in recent study

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Jun 26 2024

A recent study published in eClinical Medicine compares the effectiveness of anti-diabetes medications in reducing the risk of dementia in older diabetics.

Study: 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. Image Credit: WR7 / Shutterstock.com

Anti-diabetic drug classes

The most common second-line anti-diabetes medications include sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide 1 (GLP-1) agonists. Among these medications, sulfonylureas are the oldest and most widely used; however, both DPP-4 inhibitors and GLP-1 agonists are also being increasingly prescribed.

Sulfonylureas directly stimulate insulin secretion irrespective of blood sugar levels. GLP-1 is an incretin, which is a hormone released in response to food intake that increases insulin release.

GLP-1 receptor activation by GLP-1 or a GLP-1 agonist promotes insulin secretion, reduces glucagon secretion, and causes delayed gastric emptying and, subsequently, a feeling of fullness. DPP-4 inhibitors maintain higher GLP-1 levels for longer periods by suppressing its breakdown by DPP-4.

Previous randomized controlled trials (RCTs) have demonstrated that GLP-1 agonists are more protective against cognitive impairment and dementia than placebo. However, these RCTs were relatively small, and there is little real-world evidence to support these observations.

What did the study show?

The current study included 81,369 Swedish residents at least 65 years of age with T2DM. A total of 32,216, 43,850, and 12,351 study participants were prescribed sulfonylureas, DPP-4 inhibitors, or GLP-1 agonists, respectively. All study participants were monitored for up to 10 years to detect the onset of dementia, with a mean follow-up period of 4.3 years.

New dementia developed in 4,607 individuals, 2.3%, 4,2%, and 7.7% of whom were prescribed GLP-1 agonists, DPP-4 inhibitors, and sulfonylureas, respectively. The respective incidence rates were 6.7, 11.8, and 13.7 for every 1,000 person-years (PY).

Thus, the highest incidence of dementia occurred among patients prescribed sulfonylureas, followed closely by DPP-4 initiators. The lowest risk was observed among those prescribed GLP-1 agonists.

Subgroup analyses

The risk of dementia was 40% lower with GLP-1 agonist treatment and 10% lower for DPP-4 inhibitors compared to sulfonylureas. GLP-1 agonists were associated with a 23% reduced risk of dementia compared to DPP-4 inhibitors. These ratios were robust, even after adjusting for demographic and comorbidity factors, as well as prior medication usage.

About 30% of patients prescribed GLP-1 agonists were associated with satisfactory adherence rates, compared to 40% and 16% of those taking DPP-4 inhibitors and sulfonylureas, respectively. GLP-1 agonists were associated with 60% protection against dementia compared to sulfonylureas and DPP-4 inhibitors, both of which were not associated with any differences in dementia rates.

Sensitivity analyses

When restricted to those who ever used insulin, GLP-1 agonists were associated with a protective effect against dementia as compared to DPP-4 inhibitors. For metformin-only users, GLP-1 agonists provided the same protective effect as compared to both DPP-4 inhibitors and sulfonylureas.

Over a five-year period, GLP-1 agonist initiation could reduce dementia risk in diabetics by 14 for every 1,000 PY as compared to sulfonylureas. When compared to DPP-4 inhibitors, this drug class reduced the risk by four for every 1,000 PY.

Conclusions

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.”

The current study provides the first direct comparison of the three-drug categories in older diabetes patients on a national level. The study findings agree with previous RCTs reporting 54% protection against dementia by GLP-1 agonists. However, the present study had a better design, as it compared new GLP-1 users with patients who used the other two drug classes, thus increasing the reliability of the effect estimates.

The same effect was not observed with DPP-4 inhibitors. The difference between these two drug categories could be due to the direct activation of GLP-1 receptors by GLP-1 agonists, whereas DPP-4 inhibitors rely on endogenous GLP-1 to produce their effect. GLP-1 agonists also promote weight loss and have cardiovascular benefits, unlike DPP-4 inhibitors.

GLP-1 agonists can cross the blood-brain barrier to activate GLP-1 receptors, thus ensuring homeostasis of important neuroprotective processes that are altered in neurodegenerative disease. GLP-1 receptor activation in the brain modulates neuroinflammation, oxidative stress, cell death through apoptosis, and dysregulated glucose metabolism, all of which protect against dementia.

Nevertheless, future studies are needed to compare these drug classes with placebo in a more diverse patient population.