Great find, Chris! However, as you know, the devil is in the details. The study you cited showed that the magnesium level elevations caused by SGLT2iās are not limited to diabetics. Thatās very important. But I see one significant limitation here - all four cases discussed in that study was in individuals who were severely magnesium depleted (as a result of cancer treatment meds etc.). So they all had strong hypomagnesia. Are we sure that if they had normal levels of serum magnesium, the SGLT2is would have the same effect on magnesium levels? Itās the old black box problem - the inputs are different.
But is this merely speculation, or is there reason to perhaps think that there may be something to my observation? I think yes, there may be, given the evidence below:
SGLT2 inhibitors increase low serum magnesium levels in patients with chronic kidney disease immediately after treatment
The key passage is here, which I bolded:
"Results: Median eGFR and mean serum Mg2+ at baseline were 33.5 mL/min/1.73 m2 and 2.03 mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1 month after treatment compared with those at baseline and persisted over 6 months, with an overall mean change of 0.13 mg/dL from baseline to 6 months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid-base status, were independently associated with these changes.
Conclusions: SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis."
So, they broke down the patients into three groups with different levels of serum magnesium. The SGLT2i had a strong impact of elevating the magnesium levels in those with low levels at baseline but they did not have this effect on those with a higher level of magnesium at baseline.
Note that in the study you cited, they didnāt have anybody with higher levels of magnesium, so that effect of the SGLT2i elevating magnesium levels was present in those with severely low baseline levels of magnesium - that study said NOTHING about what happens if you have adequate levels of magnesium, do the SGLT2i still elevate your magnesium levels? The study I cited might imply that this doesnāt happen. How is that possible? Well, we do know that for example, SGLT2i are able to only get rid of glucose if the glucose levels exceed a certain threshold - itās not like they simply get rid of glucose regardless of levels and you end up hypoglycemic. Similarly, it could be that SGLT2i only hold onto magnesium from urine if the levels are low, but donāt do so if the levels are adequate or high. I donāt know that this is the case, but I can see how the mechanism could work like that. Now, the study I cited also has some limitations, such as for example this being patients with chronic kidney disease, so we donāt know if itās applicable to those with healthy kidneys. Also, I unfortunately donāt have access to the full paper.
But in line with the black box model, we canāt be sure that this finding is relevant to us - people who are not diabetic, donāt have kidney disease and have adequate/high levels of serum magnesium.
Meanwhile, here is a very interesting study - with the limitation that itās in diabetic patients! - which tackles that question at greater length:
Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials
Itās worth reading that study. Two key things I extracted from it.
1)First, there are strong individual differences between the specific SGLT2i in the respect of affecting blood electrolites: canagliflozin, empagliflozin, dapagliflozin, ipragliflozin. Worth noting!
2)The magnesium elevating effect is real, but not large - this is summed up as (my bold):
āSGLT2 inhibitors marginally increased serum magnesium levels in type 2 diabetes patients indicating a drug class effect. Further investigations are required to examine the clinical significance of elevated magnesium levels in individuals with type 2 diabetes.ā
Now, the question is: for individuals who are NOT diabetic, and who have adequate/high levels of serum magnesium, is the possible marginal further elevation of magnesium of some SGLT2i, a cause for concern? Does it mean that we should cut back on supplementing with magnesium given our situation?
Because what is the effect of higher magnesium levels in the blood? Here is a relevant passage from that study I cited above:
āAbnormally high magnesium levels are predictive of total mortality in individuals with heart failure [22], those who are critically ill [23] and those receiving haemodialysis [24]. Therefore, caution must be exercised in patients with impaired renal function, such as in severe CKD. On the other hand, both in the general population and in people with type 2 diabetes, a gradient of risk for cardiovascular disease has been observed across the normal range of serum magnesium [25], with concentrations at the higher end of the normal range associated with a lower risk of cardiovascular events [25]. Our meta-analysis found that a mean increase of 0.05 mmol/l in serum magnesium was significantly associated with a reduction in systolic BP by 2.00 mmHg and diastolic BP by 1.78 mmHg compared with placebo [26]. If serum magnesium is causally related to cardiovascular risk, a modest increase in serum magnesium could have contributed to a reduction in cardiovascular mortality observed among participants with type 2 diabetes in the EMPA-REG OUTCOME trial [19]. However, the observed changes in serum magnesium levels were, on average, within the physiological range. We do not know what proportion of individuals have serum magnesium levels above the normal range, and therefore, the clinical significance/interpretation of these data is uncertain.ā
In summary, the issue is murky. For people in our situation, specifically for people with already high levels of magnesium - close or at the upper reference range - do SGLT2i (specific the one you are using, they are all different!) elevate the magnesium levels further into abnormal territory, and what are the consequences of that, or do they not do so, per the first study in Japan that I cited, where those with higher level of magnesium experienced no further elevation from SGLT2i use.
