Metformin XR

[VA Hopeful Dr]

A question for the group.

For awhile now, I've been maxing out the extended-release metformin at 1000mg QD under the logic that immediate-release doesn't offer much benefit above 1000mg BID (analagous to lopressor 50mg BID v. toprol 50mg QD). I recently looked into that a bit more and found that much of the literature actually recommends up to 2000mg QD (can divide if GI side effects).

Do any of y'all use the higher dosing, and if so are you seeing better results without too many GI troubles?

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[deleted87716]

I tried it in the past, and didn't see any significant improvement in HgbA1c at the higher dose. I did see more GI side effects, though. Consequently, I don't tend to use metformin above 1000mg (IR or ER).

 

[septoplasty]

I Swear there was an article in the AAFP that linked saying 875 mg TID was the "best"/max dose. Not sure about the increased efficacy though, my guess is probably just more GI Upset and acidosis...

 

[Doctor4Life1769]

It's patient dependent.
Most of mine tend to tolerate 1000mg BID (IR)
However, I do have some on 500/day or 500 BID due to GI side effects.
Honestly, I don't think I've ever seen improvement with HbA1c on metformin (IR or ER).
I see improvement when patients make conscientious efforts to improve diet and lifestyle habits.
The medication I have seen improvement with is Januvia and similar DPP-4 inhibitors.

 

[VA Hopeful Dr]

I Swear there was an article in the AAFP that linked saying 875 mg TID was the "best"/max dose. Not sure about the increased efficacy though, my guess is probably just more GI Upset and acidosis...

Interestingly, there's been some recent research that suggests the acidosis isn't quite as common as we once thought - especially down to GFRs of 45 or so. I'm still a bit reluctant to use it in my stage 3 CKD patients, but I bet that changes in another year or two.

 

[VA Hopeful Dr]

It's patient dependent.
Most of mine tend to tolerate 1000mg BID (IR)
However, I do have some on 500/day or 500 BID due to GI side effects.
Honestly, I don't think I've ever seen improvement with HbA1c on metformin (IR or ER).
I see improvement when patients make conscientious efforts to improve diet and lifestyle habits.
The medication I have seen improvement with is Januvia and similar DPP-4 inhibitors.

I suspect this is a residency patient population thing. Though I certainly agree that diet and exercise, if actually done, can make a huge difference.

I've actually started using Actos a fair bit as my 3rd oral (after metformin and glipizide) before going to insulin and been fairly pleased.

 

[Doctor4Life1769]

I suspect this is a residency patient population thing. Though I certainly agree that diet and exercise, if actually done, can make a huge difference.

I've actually started using Actos a fair bit as my 3rd oral (after metformin and glipizide) before going to insulin and been fairly pleased.

Probably. I don't have experience with those outside of residency setting.

I do everything I can before initiating insulin. I'll start on DPP-4 inhibitor, consider adding on a third agent, etc. Unless the HbA1c is hopelessly high with no track record of compliance or effort.

 

[KnuxNole]

It's patient dependent.
Most of mine tend to tolerate 1000mg BID (IR)
However, I do have some on 500/day or 500 BID due to GI side effects.
Honestly, I don't think I've ever seen improvement with HbA1c on metformin (IR or ER).
I see improvement when patients make conscientious efforts to improve diet and lifestyle habits.
The medication I have seen improvement with is Januvia and similar DPP-4 inhibitors.

I thought those words were only just a myth to 99% of patients 😛

 

[deleted87716]

It's patient dependent.
Most of mine tend to tolerate 1000mg BID (IR)
However, I do have some on 500/day or 500 BID due to GI side effects.
Honestly, I don't think I've ever seen improvement with HbA1c on metformin (IR or ER).
I see improvement when patients make conscientious efforts to improve diet and lifestyle habits.
The medication I have seen improvement with is Januvia and similar DPP-4 inhibitors.

TLC is obviously the best treatment. Sadly, most folks just can't seem to make it happen (which is probably why they ended up diabetic in the first place). A lifetime of bad habits is hard to change.

Metformin is always first-line for me, even in folks with IFG (once the HgbA1c hits 6.0%), as it can help overcome insulin resistance and aid in weight loss, and may slow the progression towards diabetes.

I prefer GLP-1 receptor agonists as second-line add-ons, if the patient can be convinced to inject. I've found that they're more efficacious than DPP-4 inhibitors, and also aid in weight loss. I'll use a DPP-4 if they won't inject. There's no point in using a GLP-1 and DPP-4 together (although I see people doing it), as they both work through similar mechanisms.

Actos and SGLT-2 inhibitors are third-line add-ons for me, although it's also reasonable to consider basal insulin at that point.

I try to avoid sulfonylureas entirely, due to the risk of hypoglycemia and beta cell failure. Unfortunately, it's sometimes the only thing a patient can afford.

 

[Doctor4Life1769]

TLC is obviously the best treatment. Sadly, most folks just can't seem to make it happen (which is probably why they ended up diabetic in the first place). A lifetime of bad habits is hard to change.

Metformin is always first-line for me, even in folks with IFG (once the HgbA1c hits 6.0%), as it can help overcome insulin resistance and aid in weight loss, and may slow the progression towards diabetes.

I prefer GLP-1 receptor agonists as second-line add-ons, if the patient can be convinced to inject. I've found that they're more efficacious than DPP-4 inhibitors, and also aid in weight loss. I'll use a DPP-4 if they won't inject. There's no point in using a GLP-1 and DPP-4 together (although I see people doing it), as they both work through the similar mechanisms.

Actos and SGLT-2 inhibitors are third-line add-ons for me, although it's also reasonable to consider basal insulin at that point.

I try to avoid sulfonylureas entirely, due to the risk of hypoglycemia and beta cell failure. Unfortunately, it's sometimes the only thing a patient can afford.

Metformin is always first line, even for me. I just have not seen much of a difference with it and I do check B12 levels for those with prolonged use.
I like GLP-1 receptor agonists as well. For me, it's a matter of weight. If the patient is obese, I'll use GLP-1 agonists. If they aren't then I'll probably go with Januvia as it seems to be covered with most of my patient's insurance plans here. I don't like SGLT-2 inhibitors and would probably use Actos over that. I had some really bad side effects using Invokana in some of my patients stemming from awful dehydration. I only use sulfonylureas for those who can't afford much.

Once on insulin, my goal is to get the fasting blood sugar under control. Then, I look at post-prandial sugars and control those if needed with short acting insulin

 

[Doctor4Life1769]

I thought those words were only just a myth to 99% of patients 😛

Lol.
It's about 50/50 for me.
I don't have many on insulin. The ones who are on insulin were already on it prior to establishing with me.

I've gotten folks off metformin/2nd agents, off blood pressure meds, etc. as long as they comply with my recommendations. I don't use weight loss meds either.

 

[VA Hopeful Dr]

TLC is obviously the best treatment. Sadly, most folks just can't seem to make it happen (which is probably why they ended up diabetic in the first place). A lifetime of bad habits is hard to change.

Metformin is always first-line for me, even in folks with IFG (once the HgbA1c hits 6.0%), as it can help overcome insulin resistance and aid in weight loss, and may slow the progression towards diabetes.

I prefer GLP-1 receptor agonists as second-line add-ons, if the patient can be convinced to inject. I've found that they're more efficacious than DPP-4 inhibitors, and also aid in weight loss. I'll use a DPP-4 if they won't inject. There's no point in using a GLP-1 and DPP-4 together (although I see people doing it), as they both work through the similar mechanisms.

Actos and SGLT-2 inhibitors are third-line add-ons for me, although it's also reasonable to consider basal insulin at that point.

I try to avoid sulfonylureas entirely, due to the risk of hypoglycemia and beta cell failure. Unfortunately, it's sometimes the only thing a patient can afford.

If I can convince a patient to inject, I'd just as soon use insulin. The patients I had lose weight on the GLP-1s were mostly due to the nausea it gave them. That said, endocrinology seems to really like them so if my patients could afford them I would certainly consider it.

I'm not sure if its true, but the PharmD in residency talked at length about how glipizide and I think glimepiride only tended to really squeeze the pancreas (as she put it) post-prandially, so somewhat less hypoglycemia. My personal experience also has the XR version doing a little better on top of that. All of this is in the younger crowd, of course. Beta cell burnout is an issue, but that's going to happen to these folks anyway - we're just speeding it along slightly.

Truth be told, I never used Actos until my current practice - its the only other generic besides metformin and SU that my patients can afford. But I do like the mechanism, especially if I end up having to put someone on insulin.

I have yet to prescribe an SGLT-2. The mechanism just seems like a really bad idea to me. Plus the whole euglycemic ketoacidosis that's being reported bothers me...

 

[deleted87716]

PharmD in residency talked at length about how glipizide and I think glimepiride only tended to really squeeze the pancreas (as she put it) post-prandially, so somewhat less hypoglycemia.

He's right in that the 3rd-generation drugs were a bit less problematic, and once-daily dosing is preferable to multiple daily doses. Amaryl (glimepiride) is the only sufonylurea I'll write.

 

[styphon]

I use metformin up to 2.5gm for regular release, and 2.0gm for extended release.
I titrate very slowly to lessen GI side effects.

I have had great weight loss in paitnets with GLP, specifically Bydureon as it is only once a week injections.
I would love to use a DPPIV/GLP for 2nd line but insurance companies fight me tooth and nail.

 

[dozitgetchahi]

TLC is obviously the best treatment. Sadly, most folks just can't seem to make it happen (which is probably why they ended up diabetic in the first place). A lifetime of bad habits is hard to change.

Metformin is always first-line for me, even in folks with IFG (once the HgbA1c hits 6.0%), as it can help overcome insulin resistance and aid in weight loss, and may slow the progression towards diabetes.

I prefer GLP-1 receptor agonists as second-line add-ons, if the patient can be convinced to inject. I've found that they're more efficacious than DPP-4 inhibitors, and also aid in weight loss. I'll use a DPP-4 if they won't inject. There's no point in using a GLP-1 and DPP-4 together (although I see people doing it), as they both work through similar mechanisms.

Actos and SGLT-2 inhibitors are third-line add-ons for me, although it's also reasonable to consider basal insulin at that point.

I try to avoid sulfonylureas entirely, due to the risk of hypoglycemia and beta cell failure. Unfortunately, it's sometimes the only thing a patient can afford.

Bingo.

I've definitely seen some A1c improvement with metformin, although these pts usually are the people who are also starting to exercise and eat better as well.

I've not been overly impressed with DPP-4 inhibitors. GLP-1 agonists, however, are a different story - exenatide has been very useful for some of my patients, and the weight loss is very real with it as well.

I wish I could use SGLT-2 inhibitors...in my county hospital clinic, I'm basically limited to metformin or glipizide for most pts and can occasionally get sitagliptin and exenatide if I fight for it (aside from insulin, of course). Pioglitazone is also available, but I never use it.

 

[Doctor4Life1769]

Bingo.

I've definitely seen some A1c improvement with metformin, although these pts usually are the people who are also starting to exercise and eat better as well.

I've not been overly impressed with DPP-4 inhibitors. GLP-1 agonists, however, are a different story - exenatide has been very useful for some of my patients, and the weight loss is very real with it as well.

I wish I could use SGLT-2 inhibitors...in my county hospital clinic, I'm basically limited to metformin or glipizide for most pts and can occasionally get sitagliptin and exenatide if I fight for it (aside from insulin, of course). Pioglitazone is also available, but I never use it.

Tell me how the MOA for an SGLT-2 inhibitor is at all a good idea for long-term control of blood sugar?

 

[deleted87716]

Tell me how the MOA for an SGLT-2 inhibitor is at all a good idea for long-term control of blood sugar?

Weight loss.

 

[Doctor4Life1769]

Weight loss.

I'd pick a GLP-1 agonist over an SGLT-2 inhibitor for weight loss benefits.
I'm not so sure it's a great idea to over work the kidneys by excreting out sugar.

 

[deleted87716]

I'd pick a GLP-1 agonist over an SGLT-2 inhibitor for weight loss benefits.
I'm not so sure it's a great idea to over work the kidneys by excreting out sugar.

Agree, but with different mechanisms, the weight loss can be additive.

I'm not sure what you mean by "over work the kidneys." The effectiveness of their mechanism requires normal renal function, but there's no evidence (AFAIK) that SGLT-2 inhibitors could potentially worsen renal function.

 

[dozitgetchahi]

Tell me how the MOA for an SGLT-2 inhibitor is at all a good idea for long-term control of blood sugar?

Look at the data, dude (EMPA-REG-OUTCOME, to be specific). Reduced risk of cardiovascular events and mortality.

I agree that the MOA is a bit 'distasteful' - we're all trained to fight glucosuria. Initially, I wasn't thrilled with the idea either, and the UTI/genital mycotic infection/euglycemic DKA risk should definitely contraindicate these drugs for some patients. But I'd sure as hell rather use an SGLT-2 inhibitor 3rd-line than pioglitazone, which seems to cause weight gain and fluid retention...plus it seems like almost all my diabetics have CHF, which drops the PPARs in the 'no' column for these patients.

In reality, by the time I see high A1cs in patients on two oral diabetes meds, I start talking about insulin. I've rarely had much success with adding a third PO med in an attempt to stave off the needle.

 

[deleted87716]

I agree that the MOA is a bit 'distasteful'

Tastes like sugar... 😉

 

[VA Hopeful Dr]

Agree, but with different mechanisms, the weight loss can be additive.

I'm not sure what you mean by "over work the kidneys." The effectiveness of their mechanism requires normal renal function, but there's no evidence (AFAIK) that SGLT-2 inhibitors could potentially worsen renal function.

Yeah the evidence has yet to bear out anything too bad for renal function but I just can't believe that dumping lots of sugar into the urinary tract isn't going to cause problems.

 

[VA Hopeful Dr]

Look at the data, dude (EMPA-REG-OUTCOME, to be specific). Reduced risk of cardiovascular events and mortality.

I agree that the MOA is a bit 'distasteful' - we're all trained to fight glucosuria. Initially, I wasn't thrilled with the idea either, and the UTI/genital mycotic infection/euglycemic DKA risk should definitely contraindicate these drugs for some patients. But I'd sure as hell rather use an SGLT-2 inhibitor 3rd-line than pioglitazone, which seems to cause weight gain and fluid retention...plus it seems like almost all my diabetics have CHF, which drops the PPARs in the 'no' column for these patients.

In reality, by the time I see high A1cs in patients on two oral diabetes meds, I start talking about insulin. I've rarely had much success with adding a third PO med in an attempt to stave off the needle.

I am super skeptical of that trial. Drug company funded with an insanely high mortality benefit compared to almost all of our other interventions.

 

[Doctor4Life1769]

Look at the data, dude (EMPA-REG-OUTCOME, to be specific). Reduced risk of cardiovascular events and mortality.

I agree that the MOA is a bit 'distasteful' - we're all trained to fight glucosuria. Initially, I wasn't thrilled with the idea either, and the UTI/genital mycotic infection/euglycemic DKA risk should definitely contraindicate these drugs for some patients. But I'd sure as hell rather use an SGLT-2 inhibitor 3rd-line than pioglitazone, which seems to cause weight gain and fluid retention...plus it seems like almost all my diabetics have CHF, which drops the PPARs in the 'no' column for these patients.

In reality, by the time I see high A1cs in patients on two oral diabetes meds, I start talking about insulin. I've rarely had much success with adding a third PO med in an attempt to stave off the needle.

The data is inconclusive at best. There are no long-term studies out there and I don't trust those studies.
Dumping sugar through the urine is just not a good idea. It has minimal effects on blood sugar, and may cause an AKI with its diuretic like effect. There are some reviews suggesting potential for 15% decline in GFR and then there's studies suggesting renal protection -- yeah, I highly doubt this is "renal protective" when the studies preface with "unknown long term studies or benefits."

 

[Doctor4Life1769]

Agree, but with different mechanisms, the weight loss can be additive.

I'm not sure what you mean by "over work the kidneys." The effectiveness of their mechanism requires normal renal function, but there's no evidence (AFAIK) that SGLT-2 inhibitors could potentially worsen renal function.

I'm not a fan for reasons stated previously.
I'd much rather start insulin at that point.

 

[j4pac]

Take women take it or is it just meant for men?

 

[FiveRivers]

I see a few posters here state that they tend to avoid Sulfonylureas due to side effect profile. However, in residency, most of the patient's that we tend to see, can not afford expensive medications. Therefore, many times I find the pattern of medications for DM essentially goes, Metformin -> Glipizide (or some sort of sulfonylurea), since the GLP 1 and DPP4 inhibitors tend to be more expensive. After the sulfonylurea (if tolerated) next step is essentially insulin.
Did the Attendings posting here get more experience post residency regarding prescribing these medications? We get a lot of lectures on them during residency, but I feel we rarely prescribe them.

 

[VA Hopeful Dr]

I see a few posters here state that they tend to avoid Sulfonylureas due to side effect profile. However, in residency, most of the patient's that we tend to see, can not afford expensive medications. Therefore, many times I find the pattern of medications for DM essentially goes, Metformin -> Glipizide (or some sort of sulfonylurea), since the GLP 1 and DPP4 inhibitors tend to be more expensive. After the sulfonylurea (if tolerated) next step is essentially insulin.
Did the Attendings posting here get more experience post residency regarding prescribing these medications? We get a lot of lectures on them during residency, but I feel we rarely prescribe them.

That was my experience in residency as well. That was the first thing I really learned in my first post-residency job - other diabetes meds. My preference at the time was Januvia - once a day, fairly easy to tolerate. I tried Byetta a few times, but the BID dosing and nausea really soured me on it - Victoza and Bydureon were new enough that I could rarely get them paid for, and SGLT-2 was brand new and so I definitely couldn't use it had I wanted to. I only really started using Actos at my current practice as the majority of my patients are cash pay and can't usually afford insulin either while Actos is pretty cheap. As long as you monitor fluid retention and do a U/A once a year as a kind of bladder cancer screening, I haven't had too much trouble with it.

 

[JustPlainBill]

Since you mentioned first post-residency job -- I was introduced to DiFranzo's Octet by another physician who had been practicing for about 10 years at the time -- had a patient walk in with an A1C of 11 -- While discussing the case with this other physician, he walked over and grabbed some samples from the sample closet consisting of 4 medications in 2 combo pills, hands them to me and says,"Dude, he needs to start this, draw xyz labs and see him in a month" -- Basically wanted to slam the guy -- I was a bit uneasy as this physician had a "fast and easy with the rules" approach ---

So, my question -- what's the consensus on DiFranzo's Octet and how do you approach it? Do you use it as a guide and tailor patient's therapy to it or what?

 

[dozitgetchahi]

I am super skeptical of that trial. Drug company funded with an insanely high mortality benefit compared to almost all of our other interventions.

Yeah. I get it. I read it and I know who funded it.

Like I said before, I don't actually use these drugs either...nobody I can treat can actually afford them. But they're another tool in the arsenal - one that I'd never be using in anything other than 3rd-line status - and quite frankly in comparison to the known side effect profiles of many other PO diabetes meds I simply don't think they're that much worse than anything else. I've admitted way too many hypoglycemic disasters in old people with sulfynoureas to be handing them out like candy. GLP-1 agonists can be very effective in my experience, but not every patient can be convinced to do injections. I don't like pioglitazone or its well-known side effect profile at all, and I simply never use it.

I'm surprised that a small sliver of my original post seems to have garnered so much backlash. Yeesh.

 

[deleted87716]

I finished residency before most of the newer agents were available, so I pretty much learned how to use them in practice. Most of my residency patients were on metformin, sulfonylureas, and insulin (usually a mix). They were pretty poorly-controlled, too, compared to my patients nowadays.

 

[Freezeout]

I always try to max out Metformin before adding anything else. I've had some good results with newly diagnosed patients (albeit small sample sizes). One patient I had go from 10.8 to 6.2 just with that and some simple diet changes.

 

[styphon]

I always try to max out Metformin before adding anything else. I've had some good results with newly diagnosed patients (albeit small sample sizes). One patient I had go from 10.8 to 6.2 just with that and some simple diet changes.

I have discussed this with the university endocrinology group as I have had multiple patients who were uncontrolled newly diagnosed, usually a1c >12, who after being put on multiple meds were then weaned off to metformin or metformin+oral alone with great results. They usually state it is "glucose toxicity", and once bringing the initial very high BG down, their body compensates and you can back off and sometimes finish treatment.