The neuroprotective role of sodium-glucose cotransporter-2 inhibitor (SGLT2i) has attracted considerable interest. The purpose of this study was to investigate the role of SGLT2i in several common neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Utilizing drug-target Mendelian randomization (MR) and colocalization, we used single nucleotide polymorphisms (SNPs) proximal to the SLC5A2 gene to analyze the influence of SGLT2i on AD, PD, ALS, and MS. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Phenome-wide association study (PheWAS) was used to probe the relationship of SGLT2i with other characteristics. Protein–protein interaction (PPI) networks were used to explore how SLC5A2 affects other proteins, and enrichment analysis was used to explore possible biological processes. The MR analysis showed that SGLT2i was negatively associated with AD (OR = 0.77, p = 0.01), PD (OR = 0.52, p = 0.04), ALS (OR = 0.60, p = 0.01), and MS (OR = 0.33, p = 0.027), indicating that SGLT2i could reduce the risk of AD by 23%, PD by 48%, ALS by 40%, and MS by 67%. The colocalization supported this conclusion. The PheWAS showed that SGLT2i was associated with body mass index and systolic blood pressure. SGLT2i is biologically closely related to the development of NDs. This study suggested that SGLT2i was able to reduce the risk of NDs. SGLT2i may perform this process through many mechanisms. This study provides a new perspective on the treatment of NDs; clinical trials and relevant experiments are necessary to further validate the neuroprotective effects of SGLT2i.
It is interesting on the neurocognitive decline side of things first for AD then for PD what some of the data shows:
Large target trial emulation (396,963 patients): Both GLP-1RAs (HR 0.67; 95% CI 0.47–0.96) and SGLT2 inhibitors (HR 0.57; 95% CI 0.43–0.75) were independently associated with lower risk of Alzheimer’s disease and related dementias (ADRD), but no difference was seen between the two classes (HR 0.97; 95% CI 0.72–1.32) (Level II evidence, JAMA Neurology 2025) 2.
Meta-analysis of observational cohorts (27 studies, >50,000 patients, 2023): Both SGLT2i (OR 0.41 [95% CI 0.22–0.76]) and GLP-1RA (OR 0.34 [95% CI 0.14–0.85]) were associated with reduced dementia risk, ranking nearly identical in efficacy (SUCRA: SGLT2i 94.4%, GLP-1RA 92.7%) II 3.
Then with Vera-Health - their discussion on PD - which needs to be updated based upon this article.
A large cohort study (~100,000 patients with diabetes) in Brain demonstrated a significantly lower risk of incident PD in patients using GLP-1 mimetics (and DPP-4 inhibitors) compared with other glucose-lowering drugs 1 II.
A systematic review and meta-analysis of 10 studies (Frontiers in Neurology, 2021) found GLP-1 agonists reduced PD risk by ~59% (HR 0.41, 95% CI 0.19–0.87, p=0.02), while evidence for SGLT2 inhibitors and other agents was absent or non-significant 2 I.
Randomized controlled trials in PD patients (Exenatide, Lixisenatide, NEJM/Lancet) demonstrated improvements in motor function and slower disease progression beyond glycemic control, supporting a disease-modifying role of GLP-1 agonists3, 4 I.
Multiple mechanistic studies suggest GLP-1 agonists act via enhanced brain insulin signaling and neuroprotection5, 6 (preclinical & translational).
In contrast, SGLT2 inhibitors show cognitive protection benefits in dementia/Alzheimer’s risk reduction 7, 8, but no convincing evidence exists yet for a direct protective effect on Parkinson’s disease development.
I try to have all my neurocognitive decline risk patients on both - but some don’t have the ability to, for cost or due to not having body weight to lose and risk of sarcopenia with pushing things. I’d like to see a bit more on PD in this space before prioritizing SGLT-2i over GLP-1’s … it would however seem very sensible, if no contraindication to run both simultaneously, which is what I try to do. For those who are already lean, I usually get away with full dose SGLT2’s without too much weight loss.
Great to hear. Are you planning on increasing from 10mg to 25mg? Why or why not? Just curious because you seem thoughtful about your interventions and I’ve been going back and forth re whether to increase the dose.
Hi All, Much tnx to such fine data/discussion as always. Bought Dapa from India (same person we all use for cheap so not married to my stash).
Empa vs Cana vs Dapa vs? I did a google some time ago and guessed Dapa had fewer side effects may have been wrong.
Admin here moved to Empa, probably for good reasons (hopefully other then possible cost?).
I have alternated taking 5mg Dap (10mg split) both / alternating with 250mg metformin at night. Night to attampt to avoid the possible fatigue and mainly to benefit from thymus gland rejuvination.
As tipped by rejuvination health coach Alex Kikel (search on youtube).
Rethinking my fatigue test maybe I need to test taking metformin at noon after feeling perky in the AM to see if I roll over. Then same experiment with dapa at noon. I was taking dapa early AM in a blender (can’t swallow pills).
I eat very low carb so I may be teasing my body with night / day hypoglycemic events un-wittingly. I need to find my lost CGM stash.
Mainly any terse summry of this wise groups preference for which SGLT2 without regard to cost or difficulty getting, assuming some lower dose since I’m low carb, zero fruit, only for anti aging.
Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial
“Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.”
SGLT2 inhibitor use was associated with a 20 % lower risk of all-cause dementia compared to DPP-4 inhibitors.
Strongest effects observed in patients >80 years and male patients.
SGLT2i showed a significant reduction in unspecified dementia but not in Alzheimer’s or vascular dementia.
Yes, almost certainly the reason. Not a problem unless high (maybe over 52 or 54?) although cutoff isn’t clear, and maybe even then not much of a problem unless there are other risk factors for arterial/venous thrombosis. And it can certainly be a positive if hematocrit is too low.
I’m at 48.2 - according to LabCorp, it’s still within their reference interval 37.5 - 51, so I figure as long as I keep adequately hydrated I should be fine.
You are golden at 48. My most recent was 53, so I stopped empagliflozin for the time being. If normalized, I’ll start back on a 1/2 dose of dapagliflozin, since unlike empa its Hct-raising property is dose-dependent.
A perk to stopping empagliflozin is only having to get up once at night to pee instead of 2 or 3(!). I’ll definitely have to weigh the sleep impairment against the potential health benefits in deciding whether to continue using an SGLT2i long-term.
Do you think it could be safe to take mirabegron to reduce awakenings and also burn fat at the same time? Or is it harmful to keep the glucose-enriched urine in the bladder?
I actually tried Mirabegron and was really disappointed when it didn’t work for me, for whatever reason.
I have desmopressin on deck to try, but it can increase risk of thrombosis so I’ve put it off for the time being, especially with my hematocrit borderline-high.
Thx for sharing! I never knew Alex was so young! I’m jealous :). And I forgot that I used to have the Wolfram app, but somehow along the way, I forgot about it. Nice to see the man behind it.
Your question prompted me to do some digging. I actually tried Vibegron (Gemtesa 75mg), which is a newer/better cousin of mirabegron, but critically, I only tried it for 30 days because I assumed at the time that the benefits would be nearly immediate. In fact, it takes a full 12 weeks for max benefit based on the clinical trials, so I feel stupid for my assumption but also now hopeful that it will work when I try it again. I’m not worried about UTIs from taking it with an SGLT2i because I’m fully immunocompetent and I’ve never had issues with UTIs even when I had severe prostate enlargement, but if I had a different history then I can see how it might be an issue.
(poke @DrFraser )