Insulin Treatment in Patients with Type 2 Diabetes

thank you for coming for the this

webinar the webinar is going to be about

insulin titration and insulin initiation

by dr. imperious that is the professor

of Emory School of Medicine and the

division of an endocrinology and work

here at Grady Hospital I will just want

to let you know that the webinar for

next month is going to be June 19th

about management of hypertension in

patients with type 2 diabetes now we're

going to talk about insulin treatment

patient with type 2 diabetes

thank you those shares well thank you

Lena thank you very much who all of you

for joining today in this very important

webinar we have over a hundred

participants around the country so it's

great and and as enough mentioned the

next time in June 19th we're going to

discuss about hypertension the new

guidelines they are so confusing the

West the goal target and what agents

should be to be used for the management

of hypertension so today we're going to

discuss about insulin tree and now and I

hope that this presentation is very

practical when do you choose what to

choose and how do you go to a judge and

of course there's also how do you

combine insulin with other agents

especially when glucose control is not a

chief let me start with this I mean I'm

a member of the professional practice

recommendation committee of the a DEA

and I chair the diabetes counseling

guidelines committee for the American

College of endocrinology we receive

funding for investigating share studies

when different companies money goes to

Emory otherwise I have no direct

conflict with any other pharmaceutical

company so when you talk about insulin I

think is good to keep in mind what

happened with better self function or

insulin secretion the impatient with

type 2 diabetes

and this is data that is derived from

the United Kingdom perspective really

studies in which you can see is that at

the time of diagnosis of diabetes which

see in the x-axis with the number 0 the

it is estimated that about half or the

beta cell function or the capacity to

produce insulin is gone in the patient

with type 2 and with progression of

diabetes the insulin secretion

diminished and the reason why this

happen is because the better

self-effacing with type 2 diabetes

undergo apoptosis of cell death more

rapidly than a patient without diabetes

so the main reason why people develop

type 2 diabetes is the inability of the

pancreas to produce enough insulin to

overcome the insulin resistant

associated with obesity so when you look

at at the beginning if you have a

patient with type 2 and you diagnosed

them early like pre-diabetes diabetes in

that phase it's very easy to control

them you had the best actor in the world

lifestyle will do it or mono therapy

with mono therapy with metformin that is

the preferable prefer agent but will

increase the racing of diabetes

metformin is not enough or sulfonylureas

of the agents are not enough and most of

the time we're going to require

combination therapy so when that this

combination therapy is needed well it

varies from patient to patient but after

3 to 6 months that somebody's not well

controlled use of combined agents and if

you look at this lives after age 9 13 to

8 to 10 years of of diabetes most people

are insulin opening so we tell our

patients that sooner or later that very

likely in the natural history of the

disease they will require and this is

where we have to accept as

and it's not that the patient is not

control because they don't take care of

themselves it's just the natural history

of the disease so in the last two years

in the last few years really this is the

ACE recommendations you see that the

first thing that we recommend is to star

or a legends lifestyle therapy for

everybody and then we go to mono therapy

and we would like everybody to be

treated with metformin because it's as

effective as most of the other medicines

is safe we have 40 50 years experience

abusing as cardiovascular protection and

if metformin is not enough three months

later we would like you to combine

metformin with G up to 180 LT 2 DP

before or all the other agents that you

see in this slide the other thing here

to your right is when does insulin is

needed so if you have a patient with a

couple of oral agents or more

importantly if you have the patient with

symptomatic diabetes so with polyuria

polydipsia weight-loss they are carbolic

because of the hyperglycemia you must

consider insulin in patient with type 2

diabetes we would like you always start

metformin in combination with basal

insulin anything under and that's the

best way to do it and metformin is

important when you start insulin because

metformin reduces the need for insulin

but about 20 to 30 percent so the

insulin dose that is requiring a daily

basis is Markley diminished with


so if I have a patient for example that

present to my clinic with glucose at 3

400 I would start metformin 500

milligrams twice a day with meals and I

peeve an insulin a basal insulin once

daily that we will discuss in the next

few minutes when do I use basal balls

only for type 1 diabetes

okay so had been

meeting with hyperglycemic crisis but

let's review how we start insulin

therapy so these are the recommendation

of the American Diabetes Association and

the American cause of endocrinologist at

we said before you start with lifestyle

changes plus one or two oral agents and

then you go to basically insulin therapy

following that how much and here is

basically insulin we would like you to

consider analog on top of NPA's however

NPH works well if you decide to use

analog the American College of

endocrinology will recommend you to look

at the hemoglobin a1c of the pace if the

hemoglobin a1c is less than eight so if

somebody's taking one or two oral agents

who contrast our insulin they were

starting point one to point two units

per kilo so it's somewhere around 6 to

12 14 units for most people and if the

hemoglobin was seized greater than eight

percent eight nine ten you start on

point 2 to point 3 units per kilo so

when do you use the point to where

elderly people patient wise home keep

the kidney compromise I'm point three

for the more of these younger patient

normal kidney function so if somebody

like me that I'm about 80 kilos I will

start myself on 20 units of insulin once

daily in combination of the oral agents

and this is shown in this life so rule

number one is that you continue the oral

ages second you are and even those of


can also be large in order a meal or

take later and you start on point to 0.3

in is pretty low and what you're going

to do you're going to look at the blood

glucose next morning the fasting blood

glucose so if you use mph that is very

good insulin in patients who are normal

kidney function eating well you're going

to start on point two point three so 20

years or 15 years and you look at the

fasting blood glucose and you'll then

you're going

to adjust the insulin daily or every

other day with twice a week increasing

the dose of insulin till the fasting

blood glucose is within your range in

this case less than 130 could be less

than 150 do you have to decide what the

fact in glucose targets should be so why

if you use NPH you must give it at the

even in those because of the short

half-life of the MTA's insulin and when

you are in your mind what you're doing

is to regulate the exaggerated hepatic

glucose production that is present

overnight in patients with type 2

diabetes if you are using large in for

you 100 you 300 if you use in datameer

or deadly tech you can give the insulin

dose at any time during the day in a

patient with type 2 diabetes

do you give 10 20 units of insulin at

any time and you talk to the patient and

ask what is preferable for each

individual and then you continue the

oral agents and these are declared in


so when you talk about basal insulin you

have the human instruments or mph that

have been around to the 1950 you have

the analogs the loan act in analogs then

you have large and you 300 you 100

datameer you 100 and we have also basic

law of biosimilar that is also you 100

and in the last five years we have the

law knocked in insulin that is you 300

they will take you 100 or you 200 so you

have a large number in reality we have

12 different formulation of insulin for

the treatment of type 2 diabetes so here

at this table and the table shows the

characteristics of each one of these

agents human instantly started working

in two to four hours impeaching about

four to ten it varies from patient to

patient then it has a duration of action

between 12 to 16 hours there are mirror

and large are not very similar

Guardian has a little longer duration of

action but not much different and in

contrast to the nth it doesn't has a

pronounced peak and this is shown in the

bottom on the different graph that we

see in this live and this is the mph the

problem with the mph that has a peak but

it worked well but the variability of

day to day is much larger than the

Damier show in the middle or the large

and shown in the right lower quadrant of

this line so how good is in pH in pH

worked very well and we have used mps in

combination with metformin for the last

40 years it has also been shown in

combination with sulfonylureas although

the reso hypoglycemia is higher if you

use MPs and sulfonylureas what you see

in these lines is data from Europe from

all data 20 years ago that is if you

have a patient take a bit time in pH

with oral agents and you see that they

reduction with metformin and MPs is

somewhere around 2 to 2.5 percent given

impedance at plates on the mph twice a

day so it worked very well

you start 15 20 units of NPH 20 no

metformin and it works very well in the

last few years in the last 12 years we

have the data from large in u-100 under

Emir and if you compare mph what is

shown here to the left versus large n

there is no difference in glycemic

control so if you titrate in pH at a

time or guardian at that time or any

time during the day and you increase the

dose progressively to achieve good

glucose control there is no different so

the efficacy of mph and Largent is very

similar and the same thing it could be

compared to their Amir in the right side

of this line but if you compare these

safety so the hypoglycemia risk between

NPS and large in or in

and their mission to the left large and

showing to the right and if you try to

achieve a fasting blood glucose less

than a hundred less than 110 you have

more hypoglycemia so if you're going to

use in pH you should not try to get yeah

you should not target a fasting blood

glucose less than 100 110 120 our target

a blood glucose fasting blood glucose

less than 140 in that case I don't get

much hypoglycemia but if you use the

analogues you can titrate through lower

blood glucose in the way that you have

less hypoglycemia so again this is how

you start in pH in the evening large and

at any time during the day you start

from 1 to point to a point two point

three dependence or hemoglobin a1c but

if you stop are let's say 15 20 units

for a patient with type 2 that's likely

it's not enough but you want to start at

a low dose because you want to prevent

hypoglycemia if you start in the higher

dose and the patient star will develop

hypoglycemia they get scared and we know

that patient have recurrent hypoglycemia

they don't titrate and they lose control

so what we want is to start low dose and

ask the patient to selfish-ass danger so

we tell the patient to increase the

insulin dose by 2 to 4 units every 3 to

5 days and the person can do that

himself and you have to teach him I ran

in the piece of paper the blood glucose

greater than 150 180 every day you

increased by 12 you two units hotel you

start on 20 you go to 22 24 26 every 3

to 5 days until you achieve goals there

are some other ways to do it you can

increase by 10% in the blood glucose

between 140 to 180 or by 20% the total

glucose total insulin those if the

fasting blood glucose greater than 180

it doesn't matter what formula you use

the patient should learn how to adjust

insulin therapy and

of course if you start 10 to 20 units is

not enough for it and this has been

shown in different studies like this one

that depicts the amount of insulin in

different studies the internal insulin

dose is somewhere around 40 to 80 unit

for most people so if you start with

just 10 20 units they need to self

adjust and this is important because in

most of the clinical studies for example

this is a meta-analysis in almost 17,500

patients the chances that somebody using

oral agents and area basically

instruments is not very good most people

do not achieve good glycemic control

only fifty percent but this is important

to keep in mind and you have to tell the

patients because the patient are

expecting that if you start insulin

they're going to be in control but

unfortunately not everybody achieve

control so you need to titrate the dose

up and of course keep in mind and the

patient should keep in mind that maybe

this is not enough and you need to have

combination therapy so why is not enough

because basal insulin control the blood

glucose during the night during the

fasting space and before meals but it

doesn't cover the postprandial glucose

excursion so if I have somebody taking

metformin is a sulfonylureas or


and you add insulin I'm going to control

the base so I'm going to control the pre

meals are going to control the overnight

low glucose but it's not going to

control the postprandial glucose

excursion and what is shown in this lies

is that the higher the hemoglobin a1c

they higher the pigs offering after

meals so if you have somebody on day so

insulin not enough you have to control

postprandial and how can you control

postprandial well you can do it with

insulin or with other agents so you can

change the patient to premix insulin or

you can are based on price or base of

also multiple those

insulin combination of basil and

rapid-acting insulin or more importantly

what we do right now is combine the

insulin with other agents so this is the

Emory algorithm that we tell our

patients how to manage patient with

premix so we start 70/30 insulin

remember this is can be analog - it can

be human insulin a human insulin is just

$25 a month a analogues are much more

expensive and if somebody you're going

to start on a 70/30

the patient is symptomatic we start on

point 2 to point 3 units per kilo and we

divide we give 2/3 of the dose in the

morning one fare in the evening so if

I'm going to start somebody on 30 units

of insulin and we start 20 units in the

morning 10 units in the evening and they

my going to ask the patient to attach

the insulin every buy two units in the

mornings on at 9:00 every two to three

days and more importantly I'm going to

continue the oral agents in most of

these places so how good is 70/30

compares to Largent with it earlier here

to the left this is study on 371 patient

with type 2 diabetes on a combination of

oral agents and you add of premix or

Largent to see that the glucose control

is very similar insulin is insulin and

bring the blood glucose down but to the

right is the rate of hypoglycemia and

you have more hypoglycemia with 70/30

compares to margin yes do titrate to a

blood glucose less than 100 110 this is

another study from Phil Raskin

in Dallas and it's also shows that they

have more hypoglycemia with premix

insulin compares to Arjun however the

other studies more recently that shows

if you don't titrate that aggressively

the difference is not much different so

you can also do low knocked in a

combination of Lord Acton and prandtl

insulin so what we call basal bolos

approach so the rapid acting insulin so

the least grow the a sporadic blue

lysine is giving before meals they pick

quite rapidly in about twenty to thirty

minute and prevent the glucose is course

enough for a meal and you keep the basal

insulin once daily so in the past we ask

the patients in baseball

most of the time what we would like to

do is what is called do a step

transition from basil to basil plus one

plus two plus three that means that you

keep basal insulin the same dose and you

are five to ten units of insulin before

the largest meal it doesn't matter now

if you go to the second largest meal it

has I don't know if you go to the full

bone base footballers approach given

basal insulin plus rapid acting insulin

before each meal and this is what the

American College of endocrinology

recommend you started the basal + 1 + 2

+ 3 + u star on five units for 10% of

the basal dose given before each meal

and you progress to how a 50% base of

50% brand of insulin and there is a

large number of studies that have shown

that glucose control is very similar if

you do from biggest balls or do progress

from basil one plus one plus two plus

three so how cool is baseball this booze

is excellent in the way that you will

increase the chances that somebody will

call from basil only 50% achieve goal if

you go to baseball is about 2/3 or 3/4

of the patient with a cheap call not

everybody not everybody but baseball is

much better but has some inconvenience

that's right the inconvenience is going

to be multiple injections of insulin per

day and patients don't like that second

weight gain in the way that insulin

tried to gain weight

tends to present an insulin game way so

- around two to three kilograms in

average and there's the reso

hypoglycemia so this is what we have

behind until very recently the analog

Delamere of collagen or the human

insulin analogs premix in the last few

years we have this lawn acting insulin

let me quickly review them for you so we

have large Indy 300 and we have de glue

take you 100 and do 200 they have a very

long half-life of about 24 hours for

Arjun and about 40 hours a 40 hours 36

hours for large in about 40 hours per

day gluten and what is happening is that

it steady state is achieved later but

the peak is very flat so it's very good

in the way that give you it's easier to

take the insulin if you don't take it at

age you can take it at 12 midnight or

even in next morning with good control

so large in you 300 it has low in

half-life duration of action about 36

hours and here you have comparative to

insulin glargine you 100 in blue is you

300 the effect is very flat must fly

flatter than patient with you 100

insulin therapy

so there are similar studies in type 1

and type 2 diabetes and if you compare

the efficacy so the ability to reduce

insulin he the hemoglobin a1c between 13

to 100 and large and you 300 there is no

difference but the rate of hypoglycemia

is much less with Clark and you 300

compared to you 100 days there are

several studies in patient with type 2

diabetes and impatient with type 2

diabetes and all of them has

that the efficacy in reducing hemoglobin

a1c is very similar to the you 100 and

in most series you decrease the

hemoglobin a1c between four and eight to

one point five milligrams so if you want

to change you 100 to you 300 to improve

glycemic control Ron you won't get that

they were as shown in this lies is that

several studies have indicated that you

300 because of the flat effects the long

duration of Marchen the rate of

hypoglycemia is reduced by about 15 to

30 percent

especially nocturnal hypoglycemic so the

reason why you will choose you 300

instead of you 100 is because of the

reduction in hypoglycemia it comes also

only in pens we don't have it in

syringes and if you want to change one

somebody from you 100 to 300 you do want

to want those conversion so you don't

need to change the dose just change the

device so what about instantly

definitely that's the new insulin and

newer insulin who has a duration of

action of I mentioned before about 40

hours half-life 3 24 25 hours and you

can be take insulin up to five days

after injections and the effect is very

flat as shown in this slide this is the

Lucas lowering effect and you see that

doses of point four point six point a

passing change so it doesn't have the

peak that we see with their Amir and we

see with larger so again if you want to

change you 100 or even ampere is too big

with it you don't do it because of you

want improve glycemic control the effect

is the same as shown in these lines in

the right upper quadrant in the left

upper quadrant

that is a short that is equal the

reduction hemoglobin a1c yeah you

titrated those until hemoglobin a1c

comes down the will is shown here in the

right is the rate of hypoglycemia and

the deck has been shown to significantly

reduce hypoglycemia compared to all of

the other incidents including you 180 it

comes in two concentrations in new 100

so 100 units per ml or you 200 200 units

per ml so good in the you 100 you can

deliver up to 80 unit per injection the

other up to 160 units per injection the

price is very similar and if you compare

you 100 with dignity a big lead egg has

significant less hypoglycemia as shown

in this devote trial pound is about a

couple years ago in that it showed that

you reduce hypoglycemia and it would be

the same for mph that's right

so Rajan is better than MPs and

reduction of hypoglycemia

Diglett egg has less hypoglycemia

compare it to you 100 and if you compare

you 100 and you 300 and dignity there is

no difference in the effects or the hypo

recipe so should we use what insulin so

we use one of the major problems that we

have especially in many areas and I work

a Grady Hospital with 32 percent of my

patient have no insurance so what about

cost classes have important factor as

shown in this life because of insulin

has increased significantly during the

last twenty to thirty years but they are

insulin especially the human insulin the

regular the NPA's the premix insulin a

70/30 with MP a 70% regular 30% that you

can get it by $25 of Walmart and inseong

pharmacies so human insulin is still

relatively cheap but if you look at the

cost of analogs

the class is somewhere well over two and

three hundred

and in many save in many areas is even

much higher so this is something that I

use I use a lot of 17th 800 mt/s at

bedtime or 1730 twice daily in many

patients and start on point two point

three units and I divide and I've

progressed if the patient have no

insurance so a the good thing about

basic policies that they achieve control

but it has multiple injections so what

do you do if the patient offer based on

insulin is not well control again just

to remind you that is because of the

postprandial glucose excursion so you

need to cover post Brando and the way to

cover post prandial is given multiple

injections a day or the other thing is

to combine basal insulin with a top-1

receptor agonist a dpp-4 or an SEO t2

inhibitors all these three ways three

regiments are effective in controlling

postprandial glucose is cursing so the

first one is top-1 this is my favorite

they are right now studies comparing

going from basal to basal follows from

basal plus one glp-1 daily or every week

and the glucose control is exactly the

same so why is that because glp-1 works

in multiple ways

it increases insulin secretion second it

reduced glucagon secretion so decrease

glycogenolysis or exaggerated hepatic

glucose production a slow down gastric

emptying so your sugar your glucose is

coarse enough for a meal is delay and of

course it's associated with decreased

appetite because of the central effect

of the top-1

in the brain so

combination of basil and GOP wine is

very attractive

GOP one has been shown to improve

hemoglobin a1c and the left decreased

body weight and merkley decreased the

insulin dose because your crew coach is

better and you have a delay in gastric

emptying it can be given once a day it

can be given once a week and there are

several once daily liraglutide the most

commonly used they live

top-1 but there are several once weekly

medications and we have a external time

once we click do like retire or

trulicity once weekly and we have

semi-retired once weekly so you need to

basil every day and once a week glp-1

these studies shows the combination of

large in bursts with placebo margin with

excellent times in yellow and you see

that the addition of exenatide

markley improved less in control by 2%

without the weight gain that we see with

basil paulo therapy so the combination

of basil and GOP one is really great

this is another Spanish that is called

LIXIL on all in which patients were

receiving oral agent and with a

randomized to receive glargine in blue

links is an entire say top-1 in orange

and the glargine mixi in black and this

is the only way that you can achieve

racemic control with hemoglobin a1c less

than 7% here you have the starting with

the hemoglobin we see about a 8.2% the

end of the treatment at 30 weeks 26th

week the hemoglobin a1c was reduced a

6.5 without an increased risk of

hypoglycemia the other thing is that we

discussed in previous meetings is that

the GOP one has been shown to be cardio


and for example this is the use of

liraglutide in the leader trial the

adding to oral agents another two

medication for diabetes it reduced the

maze outcome that included

cardiovascular death non-fatal marker

and partial or stroke so and this is

another study with similar type that

also reduce cardiovascular events so the

combination of basal insulin with

chilled pea one is the preferred way to

manage patient and instead of going to

play football the third so baseball's

premier care used love baseballs

endocrinologist do not put patient with

type two the different storage patient

with type 1 so baseball has great

efficacy most people achieve goes about

2/3 of them and we are used to do it but

basal plus top-1 have similar efficacy

at less injection that the three

shot-for-shot today they have low entry

so I pulled the Samia no weight gain and

may have cardiovascular risk with our


so cons or adverse experience baseball

have hypoglycemia weight gain

cardiovascular neutral if the GOP one of

course has the main problem that I have

is a GI adverse events about 30 percent

develop lost year during the first

couple weeks and cost cos is always a

big time consideration so what about DP

before an ACL - how well do they cover

for surrounding of glucoses course and

here you have data when they'll use OTP

before the DP before

works mainly in the post prandial state

so it could be basal with DP before

you're going to decrease the glucose

excursion after a meal and that's why

you reduce hemoglobin a1c and it's

weight neutral and cardiovascular

neutral so there are several studies


Ezio today VP before an insolent I'm now

you said a lot especially in elderly

people with the hemoglobin a1c less than

8% the Amerigo I may add a bit before

you can also try the alt two alt to work

by flashing glucose in the urine

flashing sodium in the urine has

cardiovascular protection but also

covered post Brando and here you have

the effects the combination of a co2 to

plus basal insulin okay a great effects

I'm somewhere around pronate 21.5% a

more important with no increased risk of


so excellent medications to be used in

patient with insulin so in this line and

what this is my bias and I think

represent where the American College of

endocrinology and the American Diabetes

Association will suggest what to do so

you start life changes your admit form

and you combine or relations and then

you add basal insulin and in the past we

went to basal insulin to basal follows

there is no question that right now

anytime that I see a patient with type 2

after basal insulin and we going to base

or black teal t1 or dpp-4 initial T 2

because this agent do not produce weight

gain and maybe cardio protective I hope

that this lecture has been practical and

helped you to manage patient with

diabetes the things to keep in mind are

1 diabetes is a progressive disease

characterized by diminishing

beta cell function due to beta cell

apoptosis we decrease better cells where

the cells that make insulin in the

pancreas so you start with one to peel

the three peels and at the end you must

consider insulin therapy if the

hemoglobin a1c is not our goal basically

insulin is when we recommend and it

could be NPH

at nighttime and in the evening or one

of the analogues at anytime during the

day you can also use 70/30 or premix

insulin in most of the patients starting

point two point three units per kilo and

do titrate up because the usual dose is

much more than the point two point three

kilos that a patient would require if

basal insulin is not enough you might

our insulin increasing agent you can go

to base of balls multiples injections a

day well I will call you to think that

maybe the insulin plus co2 one or dpp-4

may be better in most people the same

night as your t2 maybe better than the

use of a base of power therapy

now keep in mind one thing that most

people most people will will need

insulin sooner or later in during the

lifetime of a patient with diabetes

patient who has symptomatic diabetes

should be on insulin therapy that

doesn't mean and always combined with

metformin if you're going to start based

on internal Baseball's insulin because

that reduces the insulin requirements

during the day I appreciate your

attention and you can get credit and you

can download this lies from prone to the