P.S. It is one of myriad supreme ironies of modern drugs that SGLT-2 inhibitors INCREASE glucagon secretion by alpha cells, apparently by direct epigenetic response in these same cells. As a HNF1-alpha diabetic I have studied a LOT of the genetics. And the kidneys and endocrine pancreas are HIGHLY related to one another genetically (and hence epigenetically) – first cousins or siblings I would say. I have a 3rd rare condition of kidneys, and it is severe in both left and right, due primarily to this, just to take one example. I also have a little-recognized renal biomarker for the HNF1-alpha mutations that cause the diabetes. I found this in the obscure and recent tiny field of clinical research in monogenic diabetes. A first clinical study (2012 I think) discovered the biomarker by accident. A second clinical study (2015) confirmed it, by design. This biomarker makes my results for the eGFR screening test completely invalid (but indicating chronic kidney failure erroneously). Ever since GPs started using this in 2011 it had caused me endless problems. And I had guessed immediately that it was related to the HNF1-alpha mutations, and so I searched in a focused way every couple of years thereafter for evidence. Which I then found in 2015 (hadn’t been able to find the 2012 paper before, since this and its clinical study was not about the
“accidental” biomarker but for another biomarker of HNF1-alpha diabetes), sure enough.
So SGLT-2 inhibitors induce a highly abnormal condition of kidneys that disposes of BG excessively, disrupting/dysregulating the normal function of the renal tubules.
While at the same time FURTHER increasing already excessive HGP/HGO in the T2D. Just brilliant. Grand.
One might guess what my opinion of this latest medical miracle really is. And what I would advise (against) for any T2D.
Folding all the way back to Roger Unger and Ralph Defronzo, both at UTSW since the 1970s (Defronzo is significantly younger than the late Unger, though), Defronzo is a KOL (key opinion leader) and big advocate for SGLT-2 inhibitors. This is an extremely lucrative and comfortable role for an MD, and especially for an academic in the medical field(s). And Defronzo has played this role for many other, older diabetes “drugs” over the course of his career. Unger really never got into this kind of thing/role.
Insulin is by far the most potent hypoglycemic agent of all, in addition to being by far the oldest such med (albeit a human hormone or analog rather than a pharmaceutical). It IS the best agent, and only agent required, for ANY form of insulin-deficient diabetes (all but MODY-2 to my knowledge). Even Dr. Bernstein prescribes metformin, which I do not believe in at all. Bernstein and I agree that metformin is a very weak hypoglycemic agent.
Bernstein also prescribes thiazolidinediones and some other pharmaceutical agents in a limited number of cases of diabetes, but generally eschews hypoglycemic drugs except for insulin and metformin. Valter Longo has the same idea as I do about metformin, and thinks it is a bad idea and not a wonder drug. For exactly the same reasons of biology. But he is not a diabetologist with patients, like Bernstein. Neither am I. But I generally do not believe in efficacy or safety of overriding predominant regulatory pathways (aka negative feedbacks) of our metabolism and genetics which have evolved over millions of years in modern hominids. The dangers of this are NEVER fully understood – not even close, by anyone on earth. But when some of these ARE understood by those such as Longo, they are always frightening and worrisome. MDs do not have the time, nor the knowledge, to worry about such things, with very few exceptions (e.g. Unger, who was a pure researcher and not a practicing clinician).
I believe that many or most patients, if capable and motivated, would be wise to do the worrying in the MDs’ stead. For their own benefit.
