The impressive effectiveness of low dose GLP1-RA on stubborn HbA1C

[cl-user]

As I’ve already mentioned here I tried everything to lower my HbA1C which is as always been around 6 for the last 11 years at least. My first test was ordered by my then doctor when I was 51.
During those 11 years I’ve tried every thing from diet (including strict 0 carbs keto) to medication like Metformin, Acarbose and Empagliflozin, including every supplements supposed to help with glucose.

Nothing worked… Until I tried Tirzepatide 3 mg and then, for the first time in 11 years, my HbA1C is below 5.7% after not even 3 months.
BTW I didn’t loose weight but I think I have less fat. I will do a DEXA soon.
Edit: I posted the Dexa results here

BTW after I started rosuvastatin 20 mg, the insulin went way up but Empagliflozin started to put it back down and Tirzepatide lowered it further.

Obviously that an N of 1 anecdata but I encourage the other people with the same stubborn HbA1C issue to give it a try.

[PBJ]

Interesante. Thanks for the data.

[CronosTempi]

Very interesting - I am in your exact situation, very, very, very stubborn prediabetic despite heroic lifestyle measures (diet composition, lowering calories, intense exercise, timing etc.) and supplements and medications (metformin - total bust).

I’m trialling empagliflozin atm, I’m at 3 months of 12.5mg/day at the moment, will get a full blood panel in a few weeks. If I’m still in prediabetic A1c territory (as I expect), I’ll raise the empa dose to 25mg/day - and then have to think again, what next. My plan was to try pioglitazone first, then look to GLP-1RA. But with your testimony I might actually push up the GLP-1RA. The thing that makes me hesitant is the supposed mode of action - GLP-1RA are supposed to boost insulin… not an effect I’m interested in. I’d rather the insulin I’m already putting out (which is considerable according to my labs) be more effective, hence pioglitazone as a robust insulin sensitizer. Of course, pio is not side-effect free. Hmm.

[Joseph_Lavelle]

@cl-user

Tirzepatide lowered it further.

That is interesting. I understood GLP-1 increased insulin as a primary action (to lower blood glucose). I wonder what is happening that results in lower insulin…. Perhaps your liver is putting out less glucose so your pancreas is making less insulin. GLP-1 drugs are not insulin sensitizers.

[cl-user]

@Joseph_Lavelle

I understood GLP-1 increased insulin as a primary action

Yes and no it increases the release of insulin in reaction to the blood glucose spikes. Not the baseline insulin. Basically the acute insulin secretion goes up when needed but the chronic secretion goes down.

@Joseph_Lavelle

Perhaps your liver is putting out less glucose so your pancreas is making less insulin.

That’s the way it’s supposed to work.

@Joseph_Lavelle

GLP-1 drugs are not insulin sensitizers.

Yes but in my case I’m already very insulin sensitive. My issue is the liver glucose production set point which is too high and GLP1-RA is targeting exactly that.

[cl-user]

@CronosTempi

I’d rather the insulin I’m already putting out (which is considerable according to my labs) be more effective, hence pioglitazone as a robust insulin sensitizer. Of course, pio is not side-effect free.

As I mentioned in my reply to @约瑟夫_拉维尔, the acute insulin secretion goes up when needed but the chronic secretion goes down.

That said I’m very insulin sensitive and my insulin was low. I was dismayed to see it spike with rosuvastatin but Empagliflozin and then Tirzepatide fixed that.

Looks like rosuvastatin does cause diabetes in my case.

If your A1C does not go down with Empa you should consider trying a low dose GLP1-RA instead of increasing the dose.

[Joseph_Lavelle]

@cl-user thanks. What is telling the liver to make / release less glucose? Metformin does this but I didn’t hear about GLP-1 having this effect.

My liver makes a bit too much glucose all the time. For me it’s probably a stress response.

[cl-user]

@Joseph_Lavelle

My liver makes a bit too much insulin all the time.

You mean pancreas. The liver makes glucose but the pancreas makes the insulin and glucagon.
I asked ChatGPT to explain that better than myself so here are the mechanisms by which GLP1-RA does reduce hepatic glucose production:

@ChatGPT

GLP-1 receptor agonists (GLP1-RAs) reduce liver glucose production largely through indirect mechanisms rather than by acting directly on hepatocytes. Here’s a detailed explanation:

1. Enhanced Insulin Secretion
GLP-1 receptor activation on pancreatic beta cells increases glucose-dependent insulin secretion. The higher insulin levels help suppress hepatic gluconeogenesis because insulin is a potent inhibitor of the enzymes involved in glucose production in the liver.

2. Reduced Glucagon Secretion
At the same time, GLP1-RAs lower glucagon secretion from pancreatic alpha cells. Since glucagon stimulates hepatic glucose production, its reduction leads to less activation of gluconeogenic pathways in the liver.

3. Improved Insulin Sensitivity and Hepatic Effects
The increased insulin secretion and decreased glucagon help improve overall insulin sensitivity. Moreover, indirect effects such as weight loss (a common outcome with semaglutide) can reduce liver fat accumulation (hepatic steatosis), further enhancing hepatic insulin sensitivity and contributing to reduced gluconeogenesis.

4. Additional Central and Peripheral Mechanisms
There’s evidence suggesting that GLP1-RAs may also influence central nervous system pathways that regulate energy balance and glucose metabolism. This central regulation can further modulate hepatic glucose production, although these effects are still being elucidated.

Summary
In essence, semaglutide reduces liver glucose production by:
• Increasing insulin secretion (which suppresses gluconeogenesis),
• Decreasing glucagon secretion (which otherwise stimulates hepatic glucose production),
• Enhancing insulin sensitivity (both directly and via weight loss), and
• Potential central effects on energy and glucose homeostasis.

These mechanisms work together to lower endogenous glucose production by the liver, thereby contributing to improved glycemic control in patients with type 2 diabetes.

[Joseph_Lavelle]

Sorry. I meant glucose. I’ll correct the original post.

[PBJ]

I’ve been taking 7.5 mg of tirzepatide for at least six months and just tried 5 mg of dapagliflozin (half of a 10 mg tablet) for the first time today. I realize this medication isn’t typically meant to be split, but even at this dose, I found it quite effective.

I’m wearing a CGM and ate the exact same lunch yesterday and today to compare my blood glucose response.

• Without dapagliflozin: My blood glucose spiked to 141 mg/dL and remained elevated for hours with some fluctuations.
• With dapagliflozin: My blood glucose peaked at 118 mg/dL and steadily dropped to 88 mg/dL within 2.5 hours in a smooth, linear decline.

I have to say, I’m impressed with the results so far! Has anyone else experienced similar effects with dapagliflozin at a lower dose?

[qBx123Yk]

That’s how I would expect dapa to work : blunt glucose spikes when they get above a threshold. I’ve had the same experience. I’ve also noticed that I don’t get any glucose lowering when I eat a low carb meal because there is no spike to begin with.

For me, neither metformin nor jardiance 7.5mg helped lower my A1c, which is in the pre diabetic range. This could be because I’m already eating low carb, but that’s just my guess. The jury is still out on tirzepatide, but I should know soon with my annual tests.

[PBJ]

My HbA1C has always been in the normal range, but I’d like to lower it further. I believe the combination of a GLP-1/GIP receptor agonist and an SGLT2 inhibitor can be effective for most people. Hopefully, I and others can replicate the success of cl-user. I have a test coming up soon, so I’m looking forward to seeing the results

[Beth]

I was on metformin for a few years and it only had a slight effect on my glucose spikes according to my cgm.

My tiny doses of glp1 don’t do anything I can tell, but that is expected.

Dapagliflozin has made a tremendous difference. I’ll still break through 140 once per day a few times per week, but now it’s only once and it never goes a lot higher (to 170+). My CGM used to look like a rollercoaster. FWIW, these results are with mostly my diet of beans, berries, veggies and not eating bread, oats, rice etc. I recently tried having steel cut oats again now that my spikes are managed so well, but nope, that still sent my numbers soaring, just not as bad.

@qBx123Yk Yes, I’ve noticed no matter what I do, my glucose upon waking is always similar, medication or not. I was hoping it would lower because I live close to 100.

[PBJ]

Glad to hear you’re getting great results from dapagliflozin! I’ve had the same experience with oats. I always heard they were slow-digesting and provided “all-day energy,” but my glucose spikes tell a different story.

[Philly3458]

Did you ever have a fasting insulin test? HBA1C is not a precise test. If your RBCs live a little longer (which is not uncommon in low carb diets) you would have an artificially high Hba1c.

[cl-user]

@Philly3458

Did you ever have a fasting insulin test? HBA1C is not a precise test.

I don’t know who you are replying to but I posted the fasted insulin plot in the first post.

[cl-user]

@cl-user

BTW I didn’t loose weight but I think I have less fat. I will do a DEXA soon.

I just did that DEXA and it’s pretty cool!
3mg/week of Tirzepatide + exercise reduced my fat (from 18.3% to 14.3%) but increased the lean body mass from 78% to 82%.

[snax444]

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[snax444]

@cl-user

Looks like rosuvastatin does cause diabetes in my case.

This appears to be the case with me as well. Despite incorporating gym workouts + HIIT (and no change to any other variables), my hba1c bumped up from 5.2% to 5.8%, having taken rosuvastatin 5mg/day for 4 weeks in a row… I suspect this could be an amplified response in a highly insulin sensitive individual like me, with Fasting Insulin 2 and Fasting Glucose 90)… In general, Rosuvastatin appears to have a dose-dependent effect on glucose metabolism for the average population (although some people don’t seem to have any/much side effect even at large dose), however, for some people, even a low dose appears to significantly impair glucose homeostatis.

Fortunately for me, Bempedoic Acid + Ezetibime has no impact on my glucose metabolism, liver function and renal function. With Rosuvastatin 5mg + Bempedoic Acid 180mg + Ezetibime 10mg, I can get my LDLc down to <60 mg/dL (while coping up glucose dysregulation). With only Bempedoic Acid 180mg + Ezetibime 10mg, I can get my LDLc down to about 77 mg/dL, I may have to settle for this. Pcsk9i is neither easily accesible nor afforable, but i’ll be keen to do an experiment on it some day… And I haven’t tried Pitavastatin, which appears to have the most neutral effect on glucose metabolism

[DeStrider]

You can try adding a low-dose statin every other day (EOD). I find that acceptable in my case where atorvastatin every day was causing muscle spasms. Rosuvastatin was far worse.