Glucose lowering meds lower dementia risk

#1

This is really an interesting case of “a tale of two studies”, where one somewhat contradicts the other one to some degree.

First we have this:

GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias

https://jamanetwork.com/journals/jamaneurology/article-abstract/2831976

“Results This study included 33 858 patients in the GLP-1RA vs other GLD cohort (mean age, 65 years; 53.1% female), 34 185 patients in the SGLT2i vs other GLD cohort (mean age, 65.8 years; 49.3% female), and 24 117 patients in the GLP-1RA vs SGLT2i cohort (mean age, 63.8 years; 51.7% female). In IPTW-weighted cohorts, the incidence rate of ADRD was lower in GLP-1RA initiators compared with other GLD initiators (rate difference [RD], −2.26 per 1000 person-years [95% CI, −2.88 to −1.64]), yielding an HR of 0.67 (95% CI, 0.47-0.96). SGLT2i initiators had a lower incidence than other GLD initiators (RD, −3.05 per 1000 person-years [95% CI, −3.68 to −2.42]), yielding an HR of 0.57 (95% CI, 0.43-0.75). There was no difference between GLP-1RAs and SGLT2is, with an RD of −0.09 per 1000 person-years (95% CI, −0.80 to 0.63) and an HR of 0.97 (95% CI, 0.72-1.32).”

So here we see robust HR lowering for both GLP-1RAs and SGLT2is, and the SGLT2i certainly didn’t come off worse and perhaps even marginally better.

Which brings us to the second paper:

Cardioprotective Glucose-Lowering Agents and Dementia RiskA Systematic Review and Meta-Analysis

https://jamanetwork.com/journals/jamaneurology/fullarticle/2831975

“Among drug classes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) were associated with a statistically significant reduction in dementia, but not sodium-glucose cotransporter-2 inhibitors (SGLT2is).”

And there you have it. One can look at the differences between these to try to account for why one found an effect with SGLT2is while the other did not. Perhaps duration was a key factor.

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Canagliflozin - Another Top Longevity Drug
#2

The first one is an association study. The second one is a meta-review of RCTs.

#3

Right. But still, why is there such a difference wrt. SGLT2i? That’s interesting. You yourself have frequently posted about SGLT2i and dementia.

#4

I don’t think an RCT can find a lower rate of AD diagnosis.

As noted by the authors:

Diabetes is associated with an increased risk of dementia, expected to be primarily mediated through vascular injury, but may also increase brain atrophy through other mechanisms.53 The study hypothesis was that glucose-lowering medications associated with significant reductions in cardiovascular events would also reduce the risk of dementia, acknowledging that, in general, the magnitude of association of common vascular risk factors with dementia is lower than risk reported for cardiovascular events. For example, antihypertensive therapy is associated with a 27% relative risk reduction in stroke,54 but a 7% relative risk reduction in dementia.23 As a result, large sample sizes with extended periods of follow-up are required to detect a significant reduction in dementia risk. Animal studies suggest that GLP-1RAs may reduce dementia risk through a number of potential mechanisms, in addition to neuroprotection mediated through reduced cardiovascular risk (eg, through anti-inflammatory effects on neuronal structures, antioxidative effects, and reduction in neuronal apoptosis).55 Similarly, SGLT2is have demonstrated neuroinflammatory and antioxidative effects in addition to cardiovascular prevention.56

Trials that looked at cognition and/or AD biomarkers found benefits for empagliflozin and dapagliflozin.

Then, they note:

In this meta-analysis, a larger risk reduction in dementia was associated with randomization to receive GLP-1RAs than SGLT2i classes. This may be partly explained by differences in populations enrolled, with a higher all-cause dementia event rate noted among the control group of GLP-1RA trials compared with SGLT2i trials (0.14% vs 0.05%), with a resultant increase in statistical power to detect associations.

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#5

Other papers from this week on this topic:

Evaluating the therapeutic potential of GLP-1 Agonists in Neurodegenerative Disorders (S25.006) 2025

This comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients and 2,122,880 controls across 73 healthcare organizations. Propensity score matching was performed, resulting in 102,935 patients in each cohort.
Obese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Parkinson’s disease (RR=0.784, 95%CI=0.580–1.058), Alzheimer’s dementia (RR=0.627, 95%CI=0.481–0.817), amyotrophic lateral sclerosis (RR=0.833, 95%CI=0.360–1.929), Lewy body dementia (RR=0.590, 95%CI=0.462–0.753), multiple sclerosis (RR=0.574, 95%CI=0.358–0.922), vascular dementia (RR=0.438, 95%CI=0.327–0.588), and Wilson’s disease (RR=0.833, 95%CI=0.360–1.929). Additionally, a significant reduction in mortality was observed (HR=0.525, 95%CI=0.493–0.558).

The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis 2025

Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson’s disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

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Btw another association study previously found that dapagliflozin and empagliflozin were neuroprotective, but not canagliflozin. This seems aligned with the above paper. So grouping all SGLT2i together might lead to incorrect results depending on the share of canagliflozin users in the cohorts. GLP-1RAs might similarly display intraclass heterogeneity when it comes to neuroprotection.

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Canagliflozin - Another Top Longevity Drug
#6

Cana not neuroprotective, but dapa does not lower postprandial BG, which may be related to why Cana seems more life extending. It is hard to choose. Your experience agrees with that Dapa is a mild antidepressant. What about Cana and mood? Do you have experience, or a hinch?

#7

Very interesting forest plot, but pretty surprising. How is it that oral semaglutide is “showing up” for PD (although crazy wide CI), but injectable not - injectable is far more bioavailable. A little noisy.

#8

I’ve never tried Cana so I don’t know.

@CronosTempi: maybe oral semaglutide acts on the gut more than injections? Or maybe the differences are not significant and the graph means nothing.

#9

Another paper: Sodium-glucose cotransporter-2 inhibitors and subtype-specific dementia risk: A multinational and multiethnic cohort study 2025

Adults with T2DM initiating treatment with either SGLT2i or dipeptidyl peptidase-4 inhibitors (DPP4i) between November 20, 2004, and November 20, 2024, were included.
After 1:1 propensity score matching, 278 689 patients per group were analysed. SGLT2i use was associated with a lower incidence of overall dementia (2.9% vs. 6.7%; adjusted hazard ratio [AHR] 0.77, 95% confidence interval [CI], 0.75-0.79) and a lower risk of vascular dementia (AHR 0.80), Alzheimer’s disease (AHR 0.82) and other dementias (AHR 0.68). These associations remained consistent across age, sex, baseline glycaemic control and concurrent medication use in subgroup analyses. SGLT2i use was also linked to lower all-cause mortality (4.1% vs. 11.2%; AHR 0.66, 95% CI, 0.65-0.68). Findings were robust across sensitivity and subgroup analyses, supporting the potential neuroprotective effects of SGLT2i.

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#10

Thanks. I don’t have access to the full text. Do they specify which SGLT2i were involved in this study, and did they break them out individually for effect?

#11

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis

“We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk.”

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