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Diabetes Medications

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hello everyone this is eric strong from

strong medicine at stanford university

and today i'll be discussing medications

for diabetes

excluding insulin not because insulin is

not important but because it's

so important that it's deserving of a

video entirely of its own

by the end of this video you'll be able

to describe the mechanism of action of

hypoglycemic medications

list any secondary indications and major

side effects

and most importantly you'll be able to

choose an appropriate

initial treatment regimen for a patient

with type 2 diabetes

in order to get the most out of this

video i recommend some background

knowledge of how the body regulates

glucose levels

such as my video on the physiology of

insulin and glucagon

link in the description but this is not

essential since i'll very briefly recap

the highlights

glucose homeostasis is the process of

maintaining the body's glucose

within a safe and appropriate range it's

largely controlled by the actions of two

hormones

insulin and glucagon any process which

increases insulin release or activity

lowers the blood sugar while anything

that decreases insulin's release or

activity

raises blood sugar abnormalities of

glucagon

secretion also impact blood sugar but

these are far

more rare however the insulin glucagon

paradigm of glucose homeostasis

is a significant oversimplification of

the process

there are at least seven other hormones

involved

which regulate the secretion of insulin

either directly

or indirectly this diagram is discussed

in detail in my insulin and glucagon

video

but if we strip away all but the

essentials necessary

to understand treatment we are left with

this

we have three remaining hormones to

worry about these include the incritin

hormones

gip and glp1 which are secreted by the

intestines in response to the ingestion

of fat and carbohydrates both of these

stimulate

insulin release glp1 in particular

slows gastric emptying and promotes

satiety

and both of the incritin hormones are

inactivated by the enzyme

dpp4 there's also a hormone called

amylin which is co-secreted with insulin

by pancreatic beta cells

in response to a glucose load and acts

to inhibit glucagon

there are five classes of diabetic

medications which act

on these pathways first are the

so-called

insulin secretogs which include the

sophomore ureas

which all end in the suffix ide and

maglitanides which all end in glenide

these drugs directly trigger pancreatic

beta cells to secrete insulin

glp1 receptor agonists which all end

in tide do what you might imagine them

to do

they increase insulin release and

decrease glucagon release

but since glp-1 also causes early

satiety

these meds also lead to weight loss the

average loss is relatively modest

at 1.5 to 2.5 kilograms or about four to

five pounds

but it is a nice side effect for most

patients

the inhibitors of dpp-4 all end in

gliptin

and predictably have a similar effect as

the glp-1 receptor agonists

but are a little less effective

including being weight neutral

last relevant to these pathways there is

the category of amylin

analogues of which there is one

currently approved called pramlitide

however this injected medication is only

approved for patients who are also on

meal time

insulin and is rarely used so i won't be

discussing it further today

beyond the pancreatic hormonal pathways

there are four more medication classes

that affect glucose homeostasis

sglt2 inhibitors which all end in the

suffix

glyphlosin decrease the reabsorption of

filtered glucose in the renal tubules

thiazo lighting diones commonly known as

tzds or

glutazones after their suffix increased

tissue sensitivity to insulin

there are alpha glucosidase inhibitors

such as acarbose

which decreases carbohydrate absorption

in the intestines

this is actually neither an effective

nor widely used medication

and therefore won't be discussed further

and the last class of diabetes

medication is actually by an enormous

margin

the most prescribed the biguanides of

which there currently is one

metformin which acts via multiple

mechanisms

at this point of those nine medication

classes i'm going to go through the five

most important ones

in more detail in descending order of

their current importance

before concluding with a discussion of

how to choose which one or ones

to use for an actual patient and we're

starting with the biguanides

which have an interesting history not

just because they have

a beginning as herbal remedies from the

middle ages but because

the one drug metformin may set the

record for the longest duration between

initial discovery

and eventual us approval metformin and

its glucose lowering properties

were originally discovered in 1922 but

unfortunately this discovery

went largely unrecognized as it was

overshadowed by the first use of insulin

to treat diabetes in that same year

there was some additional

scattered research here and there but

nothing caught the attention of the

broader medical community

meanwhile another biguanide called

fenformin

and its ability to lower blood glucose

was discovered in 1957.

and unlike metformin fenforman became a

popular alternative to insulin

in type 2 diabetics unfortunately it was

withdrawn from the us market

in 1978 due to growing concerns about

its association with lactic acidosis

as there remained no alternatives to

insulin other than sophano ureas at the

time

interest in metformin was rekindled

leading to clinical trials

and eventually a u.s approval in 1994.

metformin suppresses gluconeogenesis by

the liver via multiple

incompletely understood mechanisms it

increases insulin-mediated that is

post-meal

glucose utilization in peripheral

tissues

and there are various debated mechanisms

within the gut

when it's prescribed it's usually

started at 500 milligrams once daily

then if necessary up titrate it to 500

milligrams twice a day

and then again to 1 000 milligrams twice

a day

to minimize risk of side effects and

because it's most effective at blunting

post meal glucose spikes

it should be taken with meals the major

advantages of metformin

are that it is the most effective oral

agent if effectiveness is measured by

lowering a patient's hemoglobin a1c

or their average blood glucose it does

not cause hypoglycemia

and it's inexpensive contraindications

to metformin include chronic kidney

disease

over the last 10 years we've somewhat

liberalized which patients with kidney

disease can receive metformin

currently it's recommended to not

initiate it if the patient's estimated

gfr

is less than 45 and to discontinue it in

a patient once their gfr drops below 30.

metformin is also contraindicated in

severe liver disease

by a large margin the most common side

effects are diarrhea and nausea

which can be mitigated by a slow up

titration of dose over several weeks

although it's frequently said that these

side effects are only present at the

initiation of therapy

they are also anecdotally a large part

of metformin non-adherence

metformin is also associated with

vitamin b12 deficiency

and last there has been a persistent

lingering concern about metformin

causing the same lactic acidosis

that led to the downfall of fenforman

however after much study over

decades this concern appears to be

commonly overstated

and this side effect is actually quite

rare

arguably the next most notable

medication class in 2020

are the sglt2 inhibitors these inhibit

the sodium glucose co-transporter 2

in the proximal tubule blocking the

reabsorption of filter glucose

which leads to modest calorie wasting

and an osmotic diuresis

beneficial side effects for patients

with obesity and heart failure

respectively

examples of these drugs include

impagliflozin

the pagliflozin and canagliflozin

of these three impagliflozin sold under

the brand name of giardians

has the overall best risk benefit ratio

across

different populations advantages of

these meds in general include

modest weight loss impactoflozen and

canagliflozin

decreased cardiovascular mortality in

high-risk patients with type 2 diabetes

and atherosclerotic heart disease

and all three decrease heart failure

hospitalizations

and decrease the progression of

nephropathy

regarding contraindications it's

recommended to not initiate them

if the gfr is below 30 but it's okay to

continue in a patient

already on one until they become

dialysis dependent

common side effects include acute kidney

injury likely caused by

hypovolemia from the diuresis increased

risk of a variety of gu infections

they are associated with a newly

described entity of euglycemic

diabetic ketoacidosis in which patients

develop all the symptoms

signs and lab abnormalities of dka but

at near normal serum glucose levels

and lastly canagliflozin has been found

to increase the risk of lower limb

amputations and bone fractures

via an unknown mechanism

next are the glp-1 receptor agonists to

remind you

these stimulate glucose-dependent

insulin release from the pancreas

common examples include exanatide or

biata

lyric glutid doula glutide and

semiglutid

almost all these are given as

subcutaneous injections which is a major

limitation

with the exception of a once daily

tablet form of semiglutid

approved in 2019 and marketed under the

trade name

ribelsus as previously noted glp-1

agonists can lead to modest weight loss

also most of these meds have been shown

to decrease a variety of

adverse cardiovascular outcomes in

high-risk patients with atherosclerotic

heart disease

regarding contraindications these have

been associated with an increased risk

of medullary thyroid cancer in animal

models

although this has not been confirmed in

humans a personal or family history of

medullary thyroid cancer

is considered to be a contraindication

keep in mind that only a small minority

of thyroid cancers

are the medullary type because there is

an association between glp-1 receptor

agonists and pancreatitis

this is also considered to be a

contraindication

side effect for these meds are mostly gi

including the potential to worsen

pre-existing gastroparesis

and there are the previously mentioned

issues with pancreatitis and thyroid

cancer

now we are starting to get to the

medications with less of a well-defined

role in 2020

despite the fact that they are

nevertheless commonly prescribed

the dpp4 inhibitors do exactly what it

sounds like they would do

these include cytoglyptin saxoglyptin

and linogliptin

all of which are once daily tablets they

don't really have any specific advantage

over other drug classes it's recommended

to avoid combining these with glp-1

receptor agonists

they are also associated with

pancreatitis and saxoglyptin

specifically

is contraindicated in heart failure

common side effects include joint pains

and myalgias

and the aforementioned associations

and the last specific class i'll discuss

individually are the sophono ureas

these meds bind to the atp sensitive

potassium channel in pancreatic beta

cells

triggering insulin release virtually all

sephony ureas currently used

are second generation sephana ureas

including glipizide

glometeride and glyburide

their major advantage is low cost

glyburide is contraindicated in chronic

kidney disease

and the reason these drugs are near the

end of the list despite their long

history and established track record of

providing effective glycemic control

is that they cause weight gain and among

treatments

have the highest risk of causing

hypoglycemia excluding insulin

here's a summary of most of the

interventions for type 2 diabetes

which directly impact glycemic control

listed in order of typical improvement

in hemoglobin a1c

with initiation and optimization of

treatment

since diabetes is predominantly a

disorder of insulin deficiency

or insulin resistance it makes sense for

exogenous insulin to be the most

effective treatment

but interestingly lifestyle

modifications referring predominantly to

a combination of improved diet

and weight loss is as effective or more

effective

than any other medication we have

i won't read through the rest of the

chart since it's largely a summary of

what i've just been going over

but the info is here if you'd like to

pause the video

now moving on to discuss how to

determine which medication to use in a

specific patient

while this may not be the most

controversial topic in medicine

there is nevertheless disagreement in

recommendations

and even more so in how doctors actually

practice

and this brings me to the treatment

algorithm the algorithm i'll present

here

is admittedly oversimplified but is

generally consistent with

recommendations from the american

diabetes association

and the american association of clinical

endocrinologists

links to both professional society

recommendations will be in the video

description

the first considerations are the a1c and

whether the patient is directly

symptomatic from the diabetes

which is not common if asymptomatic and

with an a1c below

about 7.5 give or take lifestyle

modifications alone

is generally recommended with a recheck

of a1c in three months

remember that improved diet typically

brings the a1c down one to two points

this does of course assume that the

patient is motivated

and otherwise able to change their diet

if successful that's great continue that

plan and monitor the a1c

every three to six months if not

successful

or if lifestyle modifications are either

not possible or not desirable to the

patient

then metformin is the way to go

if a patient is asymptomatic but with an

a1c above 7.5

they should also get metformin plus

lifestyle modifications to the extent

possible

the one caveat here is that some

clinicians advocate for starting insulin

in any patient whose a1c is above 10

irrespective of symptoms now

what do you do for the patient who is

either intolerant of metformin or who

needs a second agent either because

metformin monotherapy was tried and

found to be insufficient

or because prospectively their a1c is so

high the metformin monotherapy

seems unlikely to be enough if the

patient has coronary artery disease

add a glp-1 receptor agonist or sglt2

inhibitor

if the patient has heart failure or

nephropathy add an sglt2 inhibitor

if the patient has none of the above any

non-contraindicated medication

is reasonable to add including insulin

you'll want to consider cost side effect

profile

and impact on weight allowing your

patient to be an active and engaged part

of that decision

is probably more important than the

actual drug chosen

and for any patient who is directly

symptomatic from hyperglycemia

with such symptoms being polyuria or

weight loss

insulin use at least temporarily is

strongly recommended

after initiating insulin for the first

time in addition to immediate diabetes

and insulin education the patient should

be reassessed

in person in no more than one to two

weeks just to check out how everything

is going

which actually reminds me at this point

that any patient with newly diagnosed

diabetes

irrespective of a1c should receive a

whole list of

other interventions including education

dietary counseling

iron kidney evaluations and in almost

all cases

a statin for improving their lipid

profile

though these are outside the scope of

this particular video

given the constantly changing landscape

of diabetes treatment

i'm going to end by looking over the

most commonly prescribed medications in

the u.s

here are the top 16 drugs in 2017 which

is the most recent available data

there's a fair bit of variety here and

if we take away insulin and combine the

drug classes

this is what we're left with metformin

is by a huge margin

the most commonly prescribed med

followed by the stefano ureas

and then dpp4 inhibitors which may be a

little unexpected

given that the algorithm i just

discussed did not emphasize

those latter two drugs however it's my

impression

and anecdotal experience that these

numbers have shifted a lot in the last

few years

driven largely by recent large trials

and subsequently revised guidelines

this has resulted in the sglt2

inhibitors and gop-1 receptor ankonists

becoming more common and so funny urease

generally becoming less common

but as mentioned before there remains a

fair amount of variability

and i would not be too dogmatic about

any specific drug choices

other than a strong preference for

metformin as initial therapy

in most patients

that's it for this video on diabetes

medications i hope you found it to be

helpful

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