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
“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”
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.”
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
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.
Increased risk in some but not all longitudinal studies
No increased risk in RCTs
Increased risk according to MR
Given that smoking is the largest risk factors for bladder cancer: did the longitudinal studies adjust for smoking status? If not that’s potentially a massive confounder.
We also have a potential mechanism of action:
SGLT2i increase the risk of UTIs
Recurrent UTIs are associated with a higher risk of bladder cancer
The RCT’s should be powered to make the call on bladder cancer. For that to happen the trial must be large enough and long enough that bladder cancers occur in the control group at a certain frequency. Then the treatment group statistics determine if the treatment reduces or increases bladder cancer. I haven’t looked at all the studies but basically they shouldn’t have passed peer review if bladder cancers didn’t occur in the control group over the course of the trial.
Agree with your conjecture that smoking (or other risk factor) may not be adjusted for and there may be other, even unknown risk factors that MR studies don’t take into consideration. RCT’s can match treatment and control demographics more specifically.
Among the cohort, prostate cancer was diagnosed in 210 out of 45,601 SGLT2i users, corresponding to a cumulative incidence of 1.0%, in contrast to 1,880 cases among 205,395 users of oGLMs, with a cumulative incidence of 1.5%. The use of SGLT2is was significantly correlated with a reduced risk of prostate cancer based on a multivariable-adjusted HR of 0.83 (95% CI, 0.71 to 0.98). PSM analysis affirmed 18% reduction in prostate cancer risk associated with SGLT2i use (HR, 0.82; 95% CI, 0.67 to 0.99). Subgroup analyses revealed that body mass index (BMI) significantly influenced the effect of SGLT2i on prostate cancer risk, with a more pronounced reduction in the subgroup with a BMI <25 kg/m2 (P=0.037).
Thanks. I downloaded the pdf. I find it interesting that if SGLT2i decrease the risk of prostate cancer, why are they supposed to increase the risk of bladder cancer? The other thing I found counterintuitive is that there was a greater risk reduction in nonobese (under BMI 25) individuals, as I expected the opposite, since overweight and obesity tend to increase cancer risk, so the risk of PC in slimmer people should naturally be lower, therefore by percentage any further lowering of risk by SGLT2i would be smaller than in higher BMI people.
And going back to bladder cancer, there appears to be some increased risk with progressively higher BMI. Caveat: Chinese study, but from Shanghai.
Obesity and Risk of Bladder Cancer: A Dose-Response Meta-Analysis of 15 Cohort Studies
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