SGLT2 inhibitors vs. metformin for Parkinson’s disease risk reduction in type 2 diabetes 2025
SGLT2i use was associated with a 28% lower PD risk than metformin (aHR = 0.72; 95% CI, 0.62–0.84; p < 0.0001). Dementia, a positive control, also showed reduced risk (aHR = 0.73; 95% CI, 0.68–0.78; p < 0.0001), reinforcing the neuroprotective effect. Negative controls confirmed specificity. SGLT2i users had significantly lower all-cause mortality (aHR = 0.85; 95% CI, 0.83–0.89; p < 0.0001).
Nice study, thanks. The ACM benefit was small, but good to see it, 15%.
In the forest plot of figure 2, we can see that these were beneficial in statin users. And the confidence intervals were good. Does that tell us anything about statins and PD?
Do we know which specific SGLT2i are commonly used in China, or in this particular setting? I’m wondering if this is a broad class effect or there is some particular drug that predominates here.
I don’t think we can conclude anything from that.
It seems that dapagliflozin has the vast majority of the Chinese market: 2024年七大类降糖药解析：SGLT2i为何成指南首选？_摩熵医药(原药融云)
OK, so a common one used in the West. I was afraid it might be some obscure one only used in China.
I wonder about the effect in early stage PD. They got a good group of patients there, should be possible to do some data mining.
Interesting paper about MR: The paradox of SGLT2 inhibitors in heart Failure: Caution with drug target Mendelian randomization 2025
Mendelian randomization (MR) is a well-established technique in epidemiological research. Despite its utility, several challenges in drug target MR applications remain underexplored. This study investigates the association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and heart failure (HF), employing various selections of instrumental variables (IVs) for SLC5A2 and emphasizing the necessity of positive controls. Initial summary data-based MR analysis showed that increased expression of SLC5A2 (equivalent to a one standard deviation [SD] increase) was significantly associated with Type 2 diabetes (T2D) (OR: 0.76, p = 0.038). The association with HF was not statistically significant (odds ratio [OR]: 1.30, p = 0.107). Subsequently, inverse variance weighted (IVW)-MR analysis demonstrated the association between SLC5A2-mediated HbA1c (one SD increase) and T2D (OR: 1.40, p = 0.196) and HF (OR: 0.61, p = 0.026). These IVs potentially indicated the invalid of positive control. We further constructed IVs based on the mRNA expression of SLC5A2 (p < 0.001, primarily in human blood) and assessed the association of each variant with HbA1c. IVW-MR analysis revealed significant associations between SLC5A2-mediated HbA1c (one SD increase) and T2D (OR: 2.37, p = 2.30E-7) and HF (OR: 0.45, p < 0.001). Finally, we constructed IVs from the most significant SNPs within all tissues, yielding significant associations for both T2D (OR: 3.05, p = 2.30E-7) and HF (OR: 0.44, p = 0.003). Therefore, we advocate for researchers conducting MR analysis of drug targets to report their instrumental variables, comprehend the pharmacological mechanisms involved, present positive control results and cautiously interpret their conclusions.
Sodium‐glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study
“SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.”
“Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.”
Sorry, wasn’t aware of that. Like I said, we ought to have a PMID database we can input and check against. Apologies.
Separately, I do try to read whole threads, but because I read so many studies, I don’t always remember where I saw a study first - on this or some other site or on PubMed, as I access PubMed every day.
No worries at all. In this case, searching for the paper’s title would point you to the previous post. But it doesn’t always work (poke @RapAdmin to update the search and fix the bugs 
).
Anyway, this MR study is interesting but I find it weird due to the effect being so large and contradicting many longitudinal studies and some models. The previous paper pointing to the risk of MR makes me even more skeptical considering the weak institution it originates from: Canagliflozin - Another Top Longevity Drug - #1625 by adssx
“SGLT2i use was associated with a 28% lower PD risk than metformin (aHR = 0.72; 95% CI, 0.62-0.84; p < 0.0001). Dementia, a positive control, also showed reduced risk (aHR = 0.73; 95% CI, 0.68-0.78; p < 0.0001), reinforcing the neuroprotective effect. Negative controls confirmed specificity. SGLT2i users had significantly lower all-cause mortality (aHR = 0.85; 95% CI, 0.83-0.89; p < 0.0001)”
“Sodium-glucose cotransporter 2 inhibitors showed increased reporting odds ratio for bladder cancer (ROR 4.46, 95% CI 3.23-6.17) and kidney cancer (ROR 1.84, 95% CI 1.25-2.69)”
“SGLT-2is are associated with an increased risk of reporting bladder and kidney cancer. There is a need of an urgent clarification of this signal with further long-term observational studies”
*Important note: multiple other published reports show NO increase risk, or even a decreased risk in the case of renal cell carcinoma: Decreased risk of renal cell carcinoma in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors - PubMed
Thanks for sharing. Some other papers did not find an increased risk (e.g., Sodium–Glucose Cotransporter 2 Inhibitors and the Short-term Risk of Bladder Cancer: An International Multisite Cohort Study 2022, SGLT2 inhibition and three urological cancers: Up-to-date results 2024, Sodium-glucose cotransporter 2 inhibitors and cancer: a systematic review and meta-analysis 2024) but one Mendelian randomization paper confirmed the increased risk! Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A Comprehensive Mendelian Randomization Study 2024. Is it clinically meaningful though? 
Btw, be aware that PubMed will not be available July 25 for 24+ hours:
“Service Alert: Planned Maintenance beginning July 25th
Most services will be unavailable for 24+ hours starting 9 PM EDT”
Heavy users of PubMed (moi!) please prepare accordingly. Get to the papers you may want ahead of time and stock up to survive the blackout period.
Pioglitazone on its own has been flagged for possible increased risk of bladder cancer with prolonged use and dose accumulation. This was not detected here in combination with SGLT2i - cohort study out of Taiwan. Limitations apply.
The Risk of Bladder Cancer in Type 2 Diabetes Mellitus with Combination Therapy of SGLT-2 Inhibitors and Pioglitazone
“In T2DM patients without previous or active bladder cancer, the combination therapy of SGLT-2 inhibitors and Pio was not associated with newly diagnosed bladder cancer and had lower all-cause mortality.”
There’s also this very limited value study analysis - but note, again, this tends to be very noisy:
SGLT2 Inhibitors and Bladder Cancer: Analysis of Cases Reported in the European Pharmacovigilance Database
“Our study found a disproportionately high number of cases of bladder cancer among users of SGLT2is. However, observational analytical studies will be needed to confirm these results.”
Nonetheless, this association disappeared when comparing SGLT2is with other antidiabetic drugs (ROR, 0.20; 95%CI, 0.17-0.24).
But combined with MR there seems to be a risk. Then the question: is it clinically significant?
And can it be offset in anyway?
As I am using empagliflozin, and more importantly interested in using low dose pioglitazone, bladder cancer risk is of great interest to me. At the moment I am hoping that my being on rapamycin might be protective. It’s not much, but a cautious maybe.
Intravesical Delivery of Rapamycin Suppresses Tumorigenesis in a Mouse Model of Progressive Bladder Cancer
Rapamycin Inhibits In Vitro Growth and Release of Angiogenetic Factors in Human Bladder Cancer
https://www.sciencedirect.com/science/article/abs/pii/S0090429508017810
IMO MR is a nice inexpensive approach to look for associations in large numbers of people but the gold standard of placebo controlled blinded clinical trial is then used to confirm the association suggested by MR studies. I don’t think the two approaches deserve equal weight in establishing an association. I view one (MR) as a tool and the other (Randomized clinical trial) as a study to establish whether the association suggested by MR exists. Once large clinical trials of multiple study populations are available I think MR data is no longer directly relevant to the establishment of an association in part because there are so many unknown variables in MR data that could weight the data in various directions.
A long winded way of saying I believe the trial data so long as the studies are large enough to be statistically significant and are well designed. Once that is the case I don’t have a problem if MR data emerges suggesting the opposite.
