I have spent a bit more time on this (as I am looking at Iron at the moment). Brain Iron Deficiency can cause The “Wired But Tired” Feeling (Akathisia), Pseudo-ADHD (Focus & Motivation), Sleep Fragmentation, Anxiety and Panic Pica (The Ice Craving) (and RLS).
The reason is that Iron is a cofactor for Tyrosine Hydroxylase which produces dopamine. Hence you get a reduction in Tyrosine Hydroxylase activity without enough Brain iron. The medics use 75 (different units have same value) as the threshold. This is probably because if people are inflamed then ferritin will be higher, but still deficient.
If someone is trying to clear RLS then they go for 100 (units). The conventional wisdom is 50 is needed for effective brain function.
Hence there is a conflict between reducing iron levels to enable mitophagy and not reducing them so much that you end up with a shortage of iron in the brain.
Whichever way I have a blood test on Monday and I think after that I am likely to aim to increase ferritin. I may even aim for a target of 75. Again really to see what happens. I don’t have RLS or any of the other low brain iron symptoms particularly, but I can see a good reason why low ferritin should be a temporary state. I would like to have Monday’s test result before doing anything, however.
This is obviously relevant to why iron chelation would have caused symptomatic problems in PD @adssx
I’m a long-standing blood donor (60+ units over the years) as there seem to be health benefits. I have been turned away twice recently due to marginal anaemia (125), largely due to low ferritin. So I’m also looking for a sweet spot that I think is ferritin of 20-50, just so I can donate
I would not deny that there are benefits in having lower iron levels with ferritin on an uninflamed basis below 100. However, it is more complex below that and particularly below 75 and it may require a form of cycling.
Noted John.
As I’ve said before I think I have an iron absorption problem (maybe allied to gluten sensitivity, based on SNPs I have).
That said, my HsCRP remains low so not too concerned
I don’t think we really know exactly where things should lie. It is obvious that there is a point at which it is too low and a point at which it is too high. The level for brain iron looks to be higher than that for anemia. Questions that are hard to answer are the speed to which the reduction in brain levels occurs. Hence you could have a sufficiency in the brain and take ferritin below the maintenance level, but it will take a while before that will affect the brain negatively.
I can understand neurologists wanting higher ferritin, but probably this should guide GPs as well.
“ Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific GCGR knockout (LKO) mouse model. While male LKO mice exhibited normal lifespan, female LKO mice displayed a significant reduction in survival. Strikingly, and in contrast to prevailing expectations based on metabolic improvements, this shortened lifespan in females occurred despite marked enhancements in metabolic health, including reduced body weight and adiposity, preferential glucose oxidation, elevated metabolic rate, and enhanced glucose tolerance and insulin sensitivity throughout adulthood.”
In patients with type 2 diabetes (T2D) treated with ICDs, the arrhythmic effect of empagliflozin appears more pronounced in men than in women, according to a subanalysis of the EMPA-ICD trial published Jan. 22 in JACC: Asia.
The randomized, double-blind EMPA-ICD study evaluated 150 patients across 31 centers in Japan. The study included men and women aged ≥20 years with T2D and cardiovascular disease who were being treated with an ICD or cardiac resynchronization therapy defibrillator (CRT-D). The patients (83% men) were randomized 1:1 to receive either empagliflozin 10 mg daily or placebo between April 2019 and April 2021. Patients were evaluated for adverse events and clinical status every three months.
The primary endpoint, detected by ICDs/CRT-D over 24 weeks, was the change in the number of ventricular arrhythmias (VA), including nonsustained ventricular tachycardia, as well as sustained ventricular tachycardia and ventricular fibrillation.
Looking at the primary outcome in men, there was a significant reduction in the number of VA events in the treatment group while they increased in the placebo group (–2.10 events vs. +2.25 events; p<0.001). In contrast, in women there was a slight increase in VAs in the empagliflozin group while there was a slight decrease in placebo group (+0.55 vs. –0.08 events; p=0.35). This translated to a rate ratio in men of 0.33 for empagliflozin vs. placebo (p<0.001), a 67% reduction in arrhythmia events. In women, there was no significant difference between groups, with a rate ratio of 1.78 (p=0.35). Moreover, a significant interaction between sex and treatment was observed, suggesting a sex-specific treatment response (p=0.006).
Miyo Nakano, MD, et al., note several limitations to their analysis, including the small number of female participants, the short follow-up period and the lack of diversity within the patient population. Despite limitations, they write “these results suggest that sex-related differences in arrhythmic substrate, comorbidities and pharmacokinetic properties of SGLT2 inhibitors may influence treatment response.” Furthermore, research is needed to understand these sex-differences in treatment and pharmacokinetics to develop appropriate treatment strategies in women.
Zydus Lifesciences announced tentative approval from the US FDA for its Dapagliflozin Tablets (5mg and 10mg). This SGLT2 inhibitor, used for type 2 diabetes, targets a significant US market segment where the reference drug (Farxiga) reported annual sales of USD 10,486.9 million. The approval signifies Zydus’s expanding product portfolio in the crucial US market and adds to its 430 US FDA approvals. Zydus Lifesciences Secures Tentative USFDA Approval for Key Diabetes Drug
Among study subjects, 1563 (7.8%) experienced recurrent cerebrovascular events. SGLT2 inhibitor users showed lower recurrence of cerebral infarction compared to metformin users (adjusted hazard ratio=0.84, p=0.010). Among the types of cerebrovascular diseases, ischemic stroke was associated with a significantly lower risk of recurrence in SGLT2 inhibitor users than metformin users (aHR=0.70, p=0.020). In the SGLT2 inhibitor group, concurrent use of DPP4 inhibitors was associated with a reduced risk of cerebrovascular event recurrence (aHR=0.69, p=0.011).
SGLT2i exposure was associated with significantly reduced risk of suicidality (aHR 0.75, 95% CI 0.71–0.79), all-cause mortality (aHR 0.55, 95% CI 0.52–0.57), and hospitalization (aHR 0.71, 95% CI 0.69–0.72).
I don’t have access to the full paper here but I think that they looked at all SGLT2 users with BD, so those with T2D, CKD, or HF, whereas past studies usually look at T2D only.
This is in people with bipolar disorder. If you don’t have BD, you can ignore that study. Why? Because people with BD already suffer from increased ACM and not only from cause-specific mortality (such as suicide). So SGLT2i might be fixing something that’s causing increased ACM, but only in BD physiology. We don’t know that this applies to people without BD. If people with BD had the same mortality apart from causes such as suicide (against which apparently SGLT2i are effective) as people without BD, then this would be relevant to people without BD. But they don’t - they have higher ACM. Therefore we can’t say that this would necessarily apply to non-BD people (i.e. SGLT2i lowering ACM).
All-cause and cause-specific mortality among people with bipolar disorder: a large-scale systematic review and meta-analysis
“All‐cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89–2.16, k = 39). Specific‐cause mortality was highest for suicide (RR = 11.69, 95% CI: 9.22–14.81, k = 25). Risk of death due to unnatural causes (RR = 7.29, 95% CI: 6.41–8.28, k = 17) and natural causes (RR = 1.90, 95% CI: 1.75–2.06, k = 17) were also increased.”
Sure. Although it might be argued that people with BD have a different etiology of suicide than people without BD. As usual in such situations, it’s always good when such a signal (in this case lower suicide risk) is confirmed in other populations (without BD in this case), similar to how SGLT2 heart benefits were confirmed in non-diabetic people. But yes, this is nice insofar as there were some claims that SGLT2 increase depression - it seems if anything the opposite might be true (not a huge effect either way).
It’s also good that basically SLGT2i cancels out the BD excess mortality (based on the 2.02 you sent). That’s combining two different papers using different methodologies and databases, etc. But potentially if you look at the same database and if you’d see that BD + SGLT2i has a lower ACM than no BD (and no SGLT2i) then that would be a strong signal.
Absolutely. Note, the paper I posted is very robust, with huge data set, so we can be pretty confident in those numbers. At this point, the class effect of SGLT2i in various contexts is well established, and now what is of interest is which individual SGLT2i has the biggest impact on a given outcome and risk profile. After all, we as individuals take a specific drug, so we are interested in “is it dapaglifozin, or empagliflozin, or canagliflozin best for my vulnerability X”.
That doesn’t make the result correct. A friend of mine who’s doing that kind of data mining studies told me that there were so many methodology details that can change the outcomes. Since then I don’t trust anything anymore (such as excluding or not those who study abroad!)
But in this particular case, they founs “All‐cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89–2.16, k = 39)”. If it’s 1.89 and if the other paper is correct then potentially SGLT2i lower ACM vs non BD people. Not if it’s 2.16.
(such as excluding or not those who study abroad!)