SGLT-2 Inhibitors to (partially) “Starve” Glucose Dependent Cancers

[MateoBeach]

There has been many theories proposed about how to “starve cancer”. And many have gone down rabbit holes chasing unproven theories about how to do so. Unfortunately, IMO, they simply do not work. Cancers are very metabolically flexible. They will take what they need to survive and grow and adapt to whatever nutrients are available. They will eat what we eat. Staving ourselves to attempt to starve cancer is a path to poor health status, sarcopenia, wasting, cachexia.

However, that may generally be true, yet perhaps there are exceptions. There is a category of medicines used for T2 Diabetes that inhibits the growth and progression of multiple cancers. They may have a role in Prostate Cancer that has progressed to be predominantly using glucose for energy and building materials for growth. (Usually an advanced stage of mCRPC that is identified by FDG glucose PET scan showing high glucose uptake.

The medicines are called Sodium-Glucose Co-Transporter-2 Inhibitors, SGLPT-2 inhibitors. These are widely used for treatment of Type 2 Diabetes and Metabolic Syndrome not controlled on Metformin. They have an excellent safety profile and do not increase risks of cardiovascular nor progressive renal disease. The main examples are canaglifozin and dapaglifozin. These have now been shown to reduce progression in multiple cancers including gastrointestinal, pancreatic, liver, breast, endometrial and NSCLC (lung). Cell studies (in vitro) have shown positive effects on prostate cancer lines, so this is emerging.

The SGLT2 inhibitors have multiple cell signaling pathway effects. However, their main mode of action is to inhibit one of the main mechanisms in the gut for absorbing glucose. It seems that many cancers can co-opt this same transport mechanism so they can take in large amounts of glucose to fuel and provide nutrients for growth. So inhibiting this transport mechanism can help deprive the cancer of this source. This is especially important for those patients who have T2D as well as their cancer. Yet the same mechanism may be in operation for non-diabetics with glucose utilizing cancers. (As per the “Warberg effect”).

This promising line of additional therapy might not be effective at early stages of even advanced prostate cancer that predominantly utilize fats. But perhaps a positive FDG PET scan will identify the “glucose addicted” populations that may benefits. See also below about SGLPT2 inhibitor to enhance radiotherapy. Time will tell. This is a very active area of research to watch.

MateoBeach / Paul

Effects of novel SGLT2 inhibitors on cancer incidence in hyperglycemic patients: a meta-analysis of randomized clinical trials

sciencedirect.com/science/a...

The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy

nature.com/articles/s42003-...

[Ian99]

Hi Paul. Thanks for this post. It is the first time I see a way of potentially going after the FDG tumour population, by starving them of glucose. Could the SGLPT-2 inhibitors be a subsequent complement to Pluvicto?

You will be aware that many of us are fasting or planning to do so during chemo. Not to starve the cancer as such but so that healthy cells go into protective mode. Are you saying this approach is potentially a path to poor health status. The big worry is how to mitigate toxicity.

[MateoBeach in reply to Ian99]

No worry Ian! Short term fasting for chemo is an effective strategy. I was just saying that prolonged programs that have inadequate nutrients to maintain health can be problematic. For example, when I went strict ketogenic a few years back to lose excess fat. It did that very effectively, but I ended up losing a lot of lean mass (muscle) too. And yes, SGLT-2 inhibitor could possibly be a reasonable "second-strike" after Pluvicto, if FDG PET avid lesions are present. Though this is unproven, those drugs have an excellent safety profile.

[Mascouche in reply to MateoBeach]

Your muscles loss on keto surprises me since we can eat plenty of protein while on keto.

Are you sure it could not be attributed to the ADT (assuming you were on ADT at the time you were keto).

For my part, ADT was making my muscles melt to a point where I had to train hard just to not waste away. I am speaking from a size perspective as though I was getting smaller arms and legs while on ADT, my weight was going up.

Now that ADT has ended for me and that testosterone has begun to come back, I've kept my training regimen the same as during ADT, I am back on keto since June and while my weight has been going down, my muscles have been bulking up. So keto is not wasting my muscles away.

[MateoBeach in reply to Mascouche]

That’s good M. I was also doing one meal a day fasting so I could not get enough protein to preserve muscle. Now I am much more careful about protein and just moderately low carbs, about 100 g/ day carbs and 100 G protein. I have put back on 12 pounds of lean muscle mass with intense weight workouts. And body fat remains low at <20% which is the lowest 2.5% for men. Feel much better too. Thanks!

[cujoe in reply to MateoBeach]

Peter Attia dropped his fasting regime due to loss of muscle mass. Focusing on key amino acids in the diet might be a better strategy. Altho' I do find the notion that the environment in which our metabolic functions evolved was surely one with extended periods of fasting due to unavailability of food to be a compelling argument for something other than the "3-squares-a-day" we have all grown up assuming was the norm for good health.

[MateoBeach in reply to cujoe]

Indeed, K-9. Surviving periods of scarcity without starvation was essential, especially for warm-blooded big brain creatures. Thrifty phenotype and being able to switch to ketosis were important "inventions" to this end. As is nutrient sensing and PI3K/AMPK/AKT/mTOR tuning of metabolism to conditions. Difficult to hack without possible unintended consequences!

[Maxone73 in reply to Mascouche]

Well theoretically to have the ketogenic effect you should not eat plenty of prots as you are aiming at maintaining something like 5%-20%-75% of carbs-prots-fats proportions respectively, otherwise you will use also proteins as fuel (technically the amino acids that are inside proteins but still)

[MateoBeach in reply to Maxone73]

The brain requires a minimum amount of glucose to function. Somewhere around 100 g per day I estimate. If it is not present in carb intake then it will turn protein into glucose via gluconeogenesis. Absent sufficient protein in diet it will breakdown muscle protein to provide it. The path to muscle loss as both Peter Attia and I experienced.

[Mascouche in reply to Maxone73]

I agree with you Maxone73. When I mentioned "plenty" of proteins, I did not mean it as "excess" proteins but as "you won't be at risk of having a deficiency in proteins".

[Maxone73 in reply to Mascouche]

Yes yes, I just added that bit because many do not realize that keto is a high fat mid-low proteins and almost zero carbs. This said, it always looked insane to me, I prefer a low mainly plant based low carb diet…at least till they prove that keto can cure cancer

[j-o-h-n]

Those little bastards "will eat what we eat". Now if we can only get them to eat each other.....

youtube.com/watch?v=Q8Tiz6I...(Not working as expected?)

Good Luck, Good Health and Good Humor.

j-o-h-n Thursday 09/14/2023 7:02 PM DST

[Medline]

Glucose enters cells through two classes of transporters, namely the SGLT family and the GLUT (facilitative glucose transporter) family. Normally, when there is enough glucose in the blood, cancer cells only express GLUTs, but when there is not enough glucose, cancer cells are forced to overexpress SGLTs. Therefore, SGLT2 inhibitors may be synergistic with the ketogenic diet, as SGLTs are likely to be overexpressed in these patients due to blood glucose restriction.

[MateoBeach in reply to Medline]

Good thoughts. However SGLT2 is also a major mechanism of glucose absorption from the gut, lowering blood glucose levels which is how it woks in T2D and MS. So it could be effective to some degree without a ketogenic diet. It that could enhance it in theory.

[MateoBeach in reply to Medline]

PS I like the way you think Medline. 👍🏼