Why is metformin associated with lactic acidosis? Do we need to routinely stop metformin when admitting patients with Type 2 Diabetes Mellitus (T2DM) to the hospital?

Let's explore these questions by looking at the history of metformin in the following #histmed #tweetorial.
Metformin, a biguanide, works by decreasing hepatic glucose production and increasing insulin sensitivity.

It is a first-line therapy in T2DM because it's inexpensive, well-tolerated, helps with weight loss, and has very low risk of hypoglycemia.

Metformin derives from galega officinalis, a plant long used in European folk medicine.

First synthesized in the 1920s, metformin was shown to lower blood glucose in rabbits but it was soon forgotten and eclipsed by the discovery insulin.
Interest in the biguanides returned in the 1950s, but metformin was again overshadowed, this time by phenformin, which had more potent blood glucose lowering effects.
While phenformin was quite successful at lowering blood glucose levels it would ultimately be pulled from the market in 1970s due to its association with severe lactic acidosis, which was often fatal.

Why did phenformin lead to such severe lactic acidosis?

It came down to 3 factors:
1️⃣ The general mechanism of action of biguanides.
2️⃣ Phenformin's size and structure.
3️⃣ Phenformin's metabolism.
1️⃣ While the mechanism of biguanides isn't fully understood, they do inhibit pyruvate dehydrogenase and mitochondrial electron transport, which can force anaerobic metabolism.

As a result, all biguanides can cause serum lactate levels to rise.

2️⃣ While all biguanides ⬆️ lactate production, the body is usually able to handle this load without issue.

Phenformin, however, has a large lipophilic side chain which potently binds to mitochondrial membrane, causing excess lactate production.

3️⃣ The last reason phenformin leads to lactic acidosis has to do with its 10-15h half-life, which can be even longer with renal insufficiency.

Additionally ~10% of people have defects in phenformin hydroxylation which can further increase levels .

The issues with phenformin led to understandable reluctance to use metformin, which wasn't approved for use in the US until the 1990s even though it had been used safely in other countries since the 50s.

But does metformin have the same risk of lactic acidosis?
Unlike phenformin, metformin has a relatively short half-life as it is cleared through the kidneys without even being metabolized.

Metformin also binds mitochondrial membranes less potently and thus elevates lactate levels to significantly less effect than phenformin does.
While metformin does elevate serum lactate levels, the kidneys and liver are usually able to handle the increased lactate load (see tweet 8). As a result, metformin-associated lactic acidosis (MALA) is extremely rare without underlying hepatic or renal insufficiency (GFR <30)
Despite decades of use, the data we have about MALA largely comes from case reports.

In almost all cases there are other conditions that themselves can lead to lactic acidosis including heart failure, sepsis, and kidney failure.

14/ The most comprehensive review of the data comes from a 2010 Cochrane review which analyzed 347 studies and found no cases of lactic acidosis despite looking at > 70,000 patient-years of metformin use.

So, is metformin safe to use in hospitalized patients?

Many are trained to reflexively stop metformin on admission largely due to concerns about lactic acidosis. Do we need to universally stop it and deprive patients of an effective medication?
The answer, of course, is it depends.

As with MALA, the data for metformin use in the hospital are poor but given the rarity of MALA we may not need to hold it as often as we do and should individualize care.
Obviously if there is renal impairment, especially GFR <30, another lactate-producing condition, or other obvious contraindication, metformin should be held.

But once things improve or if the patient is stable, it's probably okay to continue the metformin.
18/ In summary:
💊 Metformin is an effective first-line therapy for T2DM
💊 Phenformin is a biguanide historically associated with severe lactic acidosis
💊 Metformin can also cause lactic acidosis but this is very rare those with normal kidney and liver function.
For more discussion on when to continue metformin or otherT2DM meds in hospitalized patients check out this podcast @SatyaPatelMD and I helped to produce for @COREIMpodcast!

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More from @TylerLarsenMD

31 May
1/ Did you know that you can import an Excel spreadsheet schedule into Google Calendar?

This thread is designed for new chief residents or any folks who schedule conferences/events and want to convert a spreadsheet into individual calendar events.

During my time as a @uclaimchiefs we shared a google calendar to track tasks during the week. We also scheduled conferences via shared spreadsheets.

Importing the spreadsheet allowed me to view what conference was scheduled without constantly referencing the spreadsheet.
To start we’ll need a basic spreadsheet to schedule events.

For this tweetorial we’ll use an example of a Noon Conference spreadsheet and include “Day", “Date", “Title", “Speaker", and “Notes" as headers though for this spreadsheet the headers are not critical.
Read 12 tweets
29 May
1/ Email inbox got you down?

This thread is designed for new chiefs residents (and faculty!) on a topic I got very little coaching on before my chief resident year: Email Management.

Keep reading for Tyler’s Top 10 email tips!

#TipsForNewChiefs Image
My transition to chief year was abrupt. I went from being a decent doctor to a crappy administrator overnight. In this new role I went from receiving a few junk emails/day to hundreds of emails at all hours. The following tips are strategies that helped me survive my inbox.
1️⃣ Set boundaries.

It's easy to be on your email 24 h/day- but it's okay not to be.

Unless I was chief on call I tried not reply to email past 6pm as that is family time. I also limited checking on weekends and vacation. Setting Do-Not-Disturb and downtime can be helpful. Image
Read 16 tweets
17 Jan
1/ Why are hypodermic needles and IV catheters referenced by gauge numbers?

And why does the needle diameter get smaller as the gauge number increases?

Let's explore the obscure history of IV sizing in the following #histmed #tweetorial.
2/ The gauge numbers on modern hypodermic needles are adapted from the Birmingham Wire Gauge (BWG), a system developed during the Industrial Revolution in the early 1800s to standardize the British cottage industry of iron and steel wire manufacturing.
3/ As early as the 1200s wire was made through the process of wire-drawing, which involved pulling iron rods through a conical hole in a draw-plate or gauge.

The resultant wires could then be drawn through successively smaller diameter gauges to produce thinner wire.
Read 11 tweets
18 Nov 20
Why does obesity cause a "falsely low" B-type natriuretic peptide (BNP) in patients with heart failure?

I often hear this used to explain unexpectedly low BNP results, but I've never really understood why.

Let's explore in a #tweetorial.

#medtwitter #cardiotwitter
Before we answer this question, a quick poll.

What is the main physiologic mechanism of BNP?
BNP is a hormone secreted in response to ventricular wall stretch. It binds to natriuretic peptide receptor A (NPR-A) which ⬆️ cGMP in various tissues to exert MANY effects including:
⬆️ Natriuresis
⬇️ sympathetic tone
& so much more!

Read 19 tweets
17 Apr 20
1/ "Who feels comfortable evaluating a tracheostomy?"

Today on the wards we talked trachs. Though we see patients with trachs regularly I find it is a topic that few learners are comfortable with.

The following 🧵 is my "Hospitalists' Guide to Tracheostomies"

Where are trachs placed anatomically?

Trachs are placed between the cricoid cartilage and the sternal notch around the 2nd to 4th tracheal ring. These can be placed surgically or percutaneously at the bedside.
Anatomy of a Trach

When evaluating a trach, I find it helpful to consider the following:
🔹 Diameter - Is there an inner cannula or single lumen?
🔹 Length - Is it regular size or an Extended Length Trach (XLT)?
🔹 Cuffed or cuffless?
🔹 Fenestrations present?
Read 15 tweets
18 Feb 20
Does atelectasis cause post-operative fever?

I occasionally hear atelectasis listed in the differential diagnosis for early post-op fever (EPF) but this idea has never made much physiologic sense to me.

Let's explore this question in the following #tweetorial.
Like many US medical students, I first learned this central dogma of post-op fever on my surgical clerkship through the perpetuation of a rather cumbersome and inelegant mnemonic involving the letter W.
Despite its ubiquity, however, there is little published evidence to support this idea. One of the largest systematic reviews on the topic found that in 7 of 8 studies there was no significant association between atelectasis and early post-op fever.

PMID: 21527508
Read 19 tweets

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