Treated hyperlipidemia is along a spectrum. For many people, particularly for those that have FHC, a range of agents might bring the high lipids under control. But you then don’t want to further disregulate the lipids with something that elevates them, which rapamycin might. The other aspect is what range you are aiming for in any clinical goal. If you already have atherosclerosis, or for secondary MACE prevention, you migh want to push ApoB to a very aggressive range, which might be very difficult to achieve if you have a countervailing effect rapamycin.
This is where pioglitazone enters. It is an insulin sensitizer, and insulin resistance leads to hyperlipidemia. So you want to treat IR also in order to assist in treating hyperlipidemia. And again rapamycin can exacerbate IR. This is why pioglitazone is so interesting, because of the prospect that you might derive cardioprotection from treating IR even if you don’t have hyperlipidemia, or it is successfully treated. Note, that pioglitazone is indicated precisely for IR, and not primarily for hyperlipidemia. Rapamycin increasing IR is counter to that. The question becomes whether pioglitazone can overcome the additional rapamycin driven IR on top of the primary IR, regardless of the lipid status.
First one has to define what the particular glucose disregulation is being addressed. I highly recommend the recent Ralph DeFronzo interview with Peter Attia. His point was that diabetes, prediabetes and the resultant glucose disregulation is a highly heterogenous condition. It’s the equivalent to asking “which drug treats DISEASE?”. Well, it depends on the disease, doesn’t it. The same thing here. It depends on your glucose disregulation profile. They are all very different, and throwing them all under the label “diabetes” is not helpful, because you may as well throw them all under “disease” - all will require tailored treatment as all operate along different pathways. In some contexts of glucose disregulation, rapamycin might be harmful, while in other contexts it might be helpful:
Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes
“In fact, rapamycin increased insulin sensitivity and reduced weight gain in 3 models, and decreased hyperinsulinemia in 2 models. A key covariate of this genetically-based, differential response was pancreatic insulin content (PIC): Models with low PIC exhibited more beneficial effects than models with high PIC. However, a minimal PIC threshold may exist, below which hypoinsulinemic hyperglycemia develops, as it did in TALLYHO. Our results, along with other studies, indicate that beneficial or detrimental metabolic effects of rapamycin treatment, in a diabetic or pre-diabetic context, are driven by the interaction of rapamycin with the individual model’s pancreatic physiology.”
This is the context in which we have to see the interaction of rapamycin and pioglitazone. Now recall that there are papers showing that rapamycin harms beta cells in mice (posted here before, I don’t have time to chase them down atm). Assessing whether there is interaction depends on what the mechanism of action is for pioglitazone wrt. IR:
Effects of Pioglitazone on Suppressor of Cytokine Signaling 3 Expression: Potential Mechanisms for Its Effects on Insulin Sensitivity and Adiponectin Expression
https://diabetesjournals.org/diabetes/article/56/3/795/15175/Effects-of-Pioglitazone-on-Suppressor-of-Cytokine
“In conclusion, our results indicate that SOCS3 levels are increased in the pathological conditions of insulin resistance and that pioglitazone suppresses SOCS3 expression through the activation of PPARγ.”
Well then, the question becomes, does rapamycin work synergistically along this pathway or contrary? And here we have the answer:
mTORC2 negatively regulates DC PD-L1 and IL-10 through SOCS3 and STAT3 (172.34)
https://journals.aai.org/jimmunol/article/188/1_Supplement/172.34/76378/mTORC2-negatively-regulates-DC-PD-L1-and-IL-10
“SOCS3, a negative regulator of STAT3, was reduced dramatically in mTORC1/2-inhibited, but not RAPA-exposed DC.”
It looks to me, like pioglitazone helps with IR through suppressing the SOCS3, whereas rapamycin obviates this suppression. Note that this happens in the context of inhibition of mTORC1/2. So this makes me cautious about combining pioglitazone and rapamycin, regardless of lipid status, as this pertains directly to the primary indiction for pioglitazone - treating IR.
Now again, all of this has to be seen in the light of a particular presentation and pathophysiology of your glucose disregulation. Since we don’t at present have such detailed precision medicine when applied to any one of us, it simply represents a risk. I have no idea whether I’m in the “harmed” bucket or not, but I see no reason why I should risk it. YMMV.
