The next step after Metformin - hole in my bucket?

The hole in my bucket thing is because whichever wonder drug I look at can do all these terrific things for me, but there is just one minor thing..........which I seem to have.

[This is a long post, and may get longer as I find more information.]

https://pathways.nice.org.uk/pathways/type-2-diabetes-in-adults gives some guidance.

I expect to be at the "first intensification with Metformin combination therapy" as I am on 3 * 500 mg Metformin at the moment.
I could go to 4 * 500 mg but I have Stage 3(a)CKD and the extra Metformin might make that worse.
[..but there's a hole in my bucket....]

Sulphonylurea:

The first step after Metformin, in general, seems to be a sulphonylurea.
However there do seem to be a lot of choices.
There are also warnings about increased risk of hypos if you are eating low carbohydrate.
Which I am.
I note that the sub forum isn't very active.
How do I chose which of the many sulphonylurea drugs to take?
If, of course, there is one which works well with LCHF.

Gliptins/DPP-4 inhibitor:

Aloglyptin is listed.
"It may also cause joint pain that can be severe and disabling".
Lead me to it.

"Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP),[2][3][4] which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.".
That sounds as though it might be up my street; I think one of my main issues is too much glucagon; in the morning especially.

pioglitazone:

Not with diabetic ketoacidosis; but I have blood ketones in the 1s and 2s and have been up in the 4s when fasting.
"Common side effects include headaches, muscle pains, inflammation of the throat, and swelling.[2] Serious side effects may include bladder cancer, low blood sugar, heart failure, and osteoporosis.[2][1] Use in not recommended in pregnancy or breastfeeding.[1] It is in the thiazolidinedione (TZD) class and works by improving sensitivity of tissues to insulin.".

So it could reduce Insulin Resistance, which I assume that I still have. This would be a good thing.

However I think my main problem is too much Glucagon which inhibits insulin production so increased sensitivity may be of limited use.

(Gli)Flozins/SGLT2 inhibitors:

These seem to be only allowed if a sulphonylurea doesn't work or if there is a high risk of hypoglycemia.
The NICE page doesn't seem very keen on them.
LCHF may not play well with sulphonylureas, though.
Your friends will call you Sweet Pee.
You may get thrush.
Relies on the kidneys to shift sugar via the urine, and may confuse/delay the diagnosis of diabetic ketoacidosis (high BG and high ketones combined).
See also Stage 3(a)CKD.

A number of them are listed.
Again, which one?

Glutides:

Semaglutide looks interesting.
"Semaglutide is a glucagon-like peptide-1 receptor agonist. It increases the production of insulin, a hormone that lowers the blood sugar level.[8] It also appears to enhance growth of ß cells in the pancreas, which are the sites of insulin production.[9] On the other hand it inhibits glucagon, which increases blood sugar. It additionally reduces food intake by lowering appetite and slows down digestion in the stomach.[7] In this way it works in body fat reduction.".
All good, especially the enhancement of growth of beta cells.
Not keen on weekly injections, but I could stomach that (sorry!) if the results were really good.
https://www.diabetes.co.uk/forum/threads/semaglutide.166094/#post-2091128 considers some of the up and downsides.
The one major fly in the ointment is a slight increase in the risk of retinopathy.

However there are other glutides; so which one?
Probably not ones which require daily injections as I am a wimp.

Brunneria said:

My understanding is that Metformin and Berberine are so similar in action (and effect on kedneys) that it should be an either/or use of Met or Berb, rather than both.

I’m afraid I cannot offer any opinions on the other drugs, except to hope that it doesn’t come to it, @LittleGreyCat

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Thanks for the good wishes.

I am trying to be proactive.
I know the main aim is to avoid drugs wherever possible, but after looking at the Libre results I can see what looks like an abnormal glucagon response and I am wondering if I should consider a secondary medication before my liver beats my pancreas to death.

Although there is always more that you can do, I think I have gone almost as far as is reasonable and I can contemplate long term with weight loss and diet. I am very close to the weight and waist measurement of my late teens, having lost a stone since Xmas and my last tumble off the wagon.

Over my LCHF concerns, it has been pointed out that I could increase my carbohydrate intake as a protection against hypos.
I'm not sure how I feel about that but if it gives me overall better BG control it must be considered.
I have the embarrassing memory of commenting on a thread about increasing carbs and insulin to change lipid results, for example.

"Sulphonylurea and chips for tea again Dear?" does have a dangerously tempting sound.

Then again I met a T2 who I haven't seen for a while and their approach on diagnosis was to go straight onto insulin because then they didn't have to change their lifestyle. Sadly, it wasn't going that well for them. I think perhaps falling off that particular wagon involves a longer drop.

So upping the carbs after a 10+ year battle to restrict them would be a big decision.

Well, had a very useful chat with the DSN today.
Started with the usual:
"6.6! You are doing really well!
No I'm not!!!"

I'm very close to the target of 6.5% for HbA1c and at 11+ years diagnosed and on 3 * 500 mg Metformin I suppose that is a pretty reasonable result. However I would like to be below 6.0%.

Booked for a phone chat with our GP who specialises in Diabetes. Angling for a referral to an endocrinologist but I may have to go private as my current results probably don't justify the practice shelling out.

The information so far is that nobody prescribes Sulphonylureas any more because of the risk of battering the beta cells to death.

GLP1 and SGLT2 inhibitors are the usual next step.
However there are always side effects.
The DSN's view was that at my current stage the side effects are likely to be more of a risk than my current BG levels.
I get the impression (also from this Forum) that second stage medication is only for when the risks of uncontrolled BG are higher than the risk of side effects.
I don't seem to have reached that stage yet.

I would be happier if I could discuss this with an endocrinologist who is aware of emerging treatments but there may not be anything which can improve my results without an unacceptable increase in risk.

One alternative might be to take a small dose of basal insulin before bed each night to try and control the overnight BG and dawn phenomenon, or a small dose of fast acting insulin first thing in the morning.
However I understand that T1s struggle to control DP so this may be a red herring, and anyway I am reluctant to start taking insulin because this may make my Insulin Resistance worse.

Rock and a hard place, really.

Bumping this thread as I am still going round in circles.

@JoKalsbeek @Oldvatr
Thanks for the very helpful responses.
Noting that my last HbA1c was 7.3% in old money.

Over the last couple of days I have been semi-fasting and my BG has come down (according to a scarily accurate Libre).
All I have to do is stop eating completely and I'm sorted!

Just adding to this to say that my HbA1c 6 months on was 7.0%.
This was with a lot of effort.
Still at the edge of a second medication (perhaps).

Edit:
Noting my last eGFR was 66 and rated as normal, which does increase the options.

Bumping this up again as my HbA1c is still 7.0% despite a strict LCHF diet.

The attraction of a second medication is the ability to indulge myself slightly more.

The concern is that on my current diet and Metformin my BG can drop to around 3 on the Libre and I wouldn't want anything to push it lower than that.

LittleGreyCat said:

Gliptins/DPP-4 inhibitor:

Aloglyptin is listed.
"It may also cause joint pain that can be severe and disabling".
Lead me to it.

"Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP),[2][3][4] which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.".
That sounds as though it might be up my street; I think one of my main issues is too much glucagon; in the morning especially.

Click to expand...

https://www.januvia.com/sitagliptin/what-is-januvia/

This seems to be the most modern "glyptin" on offer.
My main concern is that once my BG drops below normal to the low 4s or into the 3s then I would need glucagon to get my liver to dump some glucose and bring my sugars back up again.

My issue seems to be not just insufficient insulin secretion, but a faulty control function which allows my BG to go high then low.
Not as extreme as Reactive Hypoglycemia but under some (not all) circumstances possibly a mild imitation.

Speedbird said:

Hi LittleGreyCat,
I haven’t read the whole thread and you may have mentioned it before but
have you been checked for insulin secretion and insulin resistance?

Click to expand...

Private check a few years back.
Low normal insulin secretion and mild insulin resistance.

Speedbird said:

Ah okay, so you don’t think you are veering towards LADA?

Click to expand...

Diagnosed for over 13 years.
After a time it is probably too long to be a honeymoon period.

Realistically, even if a test showed antibodies and an immune reaction there is no way to know if this was present 13 years ago because it wasn't tested for.

Reading through this again after someone tagged it, and finding it still very illuminating.
I am currently on 4 x 500 mg Metformin and also on Aloglyptin.
I had an HbA1c of 8.3% after going completely off the dietary rails (see other threads) but pulled back to 7.3% about 6 months ago.
I've now just passed 15 years since diagnosis so not doing terribly badly.
However I have noted the link between Aloglyptin and joint pain as I have suffered from joint flare ups, and recently been diagnosed (subject to further testing) with gout.

I note that Semaglutide is currently fashionable but I don't need to lose weight (much).

I am due another HbA1c in a few weeks (6 months on from the last one) so we shall see what we shall see.