PRINCIPLES OF INSULIN THERAPY

When to start insulin?

Insulin is needed in specific types of diabetes and in certain conditions to control
blood glucose levels. The following conditions necessitate insulin therapy:
 T1DM (type 1 diabetes mellitus)
 LADA (latent autoimmune diabetes of adults)
 T2DM (type 2 diabetes mellitus long duration, failed oral medications)
 Loss of pancreatic mass: pancreatectomy, pancreatitis
 Cystic fibrosis.
Other conditions where insulin may be needed as primary therapy in patients with
diabetes:
 Severe infections
 Pregnancy
 Major surgery / trauma
 Renal failure
 Cirrhosis of liver
 Unstable congestive heart failure
 Steroid therapy
 Marked hyperglycaemia with osmotic symptoms (polyuria, polydipsia)
 Experimental: Earlier insulin therapy: to allow beta cell rest.
Insulin therapy to control blood glucose in patients with type 2 diabetes; nearly
50% to 60% beta cell mass is lost at the time of diagnosis in T2DM.
Furthermore, patients with T2DM lose about 4% to 6% of beta cell function
per year over the next six to 10 years, which is the reason why anti-diabetes
medications lose their efficacy. Hence patients cannot maintain or achieve desired
treatment goals unless insulin is added to augment the effect of OADs (oral
antidiabetic drugs).

What are the benefits of insulin therapy?

 Increased sense of well being
 Rapid reversal of osmotic symptoms, ketosis, and regain of weight
  Rapid control of blood glucose which could be fine-tuned on hourly or daily
basis
 Allowance of pregnancy in healthy mode
 Possible “beta cell rest”
 Good control of glycaemia, which may prevent or retard complications
 Support of healing process after surgery

Different insulins, as shown in Figure one and Table one, have different onset and
duration of action. A clinician should choose one or more type of insulin according
to the glycemic profile of the individual. For example, insulin aspart covers
postprandial period well if given before meals, whereas Lantus is a basal insulin
which is required once daily to help reach fasting plasma glucose control. There
are various insulin preparations available amongst which
 lispro and aspart are short acting analogues who have an onset of action of
10 to 15 minutes. That means they can be given right before a meal. They
 peak within one to two hours and have a duration of action ranging
between 2:00 to 4:00 hours.
 Regular human insulin needs to be given 30 to 60 minutes prior to a
meal which had a peak around 2 to 4 hours and duration of action of 5
to 8 hours.
 Human NPH has an onset of action of one to three hours, a peak of four
to 12 hours, and a duration of action of 10 to 20 hours.
 Amongst the basal insulins are glargine, detemir and degludec, which do
not have a peak. Their onset of action is within one to two hours and the
duration of action varies between 24 to 40 hours.
There is also available pre mixed insulins which contain NPH and regular or
lispro and aspart in a combination of 75-25%, 70-30% and 50-50%. Each of them
have a dual peak based on the analog component and the NPH. There is also a
U-500 regular insulin, which is five times more potent than the U-100 regular
insulin. Its onset of action is within one hour and duration of action can vary
between 6:00 to over 10 hours.Human regular insulin can also be used as I/V
insulin in most of the inpatient settings. The comparison of different human
insulins and insulin analogues have been mentioned in Table-1 for further review.

Insulin Duration of
Onset of action Peak (hour)
preparations action (hour)

Lispro / aspart /
10 - 25 mins 1-2 2- 4
glulisine

Regular human 30 - 60 mins 2- 4 5–8

Human NPH 1 - 3 hours 4 - 12 10 – 20

Glargine 2 - 4 hours Flat 24

 Insulin Duration of
Onset of action Peak (hour)
preparations action (hour)

Detemir 1 - 2 hours Flat 16 – 24

Degludec 1 - 2 hours Flat > 40

Premixed
(NPH/regular)
25 - 50 mins 2.4 12 – 24
Lispro 75/25
Aspart 30/70

Lispro 50/50 c/w above

U-500 regular 1 - 1.5 hours 3.5 - 8.5 6 to > 10

Table 1. Comparison of human insulins and insulin analogs

Insulin injection technique:

Many of your patients are on insulin therapy and these therapies can be basal bolus
regimen, split-mixed regimen and basal therapy. So, these therapies are given by
different modes of delivery and the different modes of delivery will be pen or
syringe or insulin pump.
So, when it comes to insulin therapy, you should ensure that your patient is
injecting the insulin properly and how do you ensure about it? You have to educate
your patient about different modalities which are involved in this procedure. So,
the first part is about the storage of insulin. The insulin should be stored at
optimum temperature. It should be between 2 to 30° of centigrade. And it should
be kept in the in the fridge. Basically, it is kept in the door of the fridge. It should
not be refrigerated at any given point of time. The insulin should not be thawed at
any given point of time. And the patient should be encouraged to use the insulin
which is fresh and they have to label the insulin whenever they are using it for the
first time. The best site to inject the insulin is the abdomen because it contains a lot
of subcutaneous fat. The insulin is injected in the subcutaneous fat. So, you should
always tell your patient how to inject the insulin. they have to keep two fingers
away from the navel on both the sides and all the areas of the abdomen can be used
to inject the insulin. The second-best option is the outer surface of the thigh, again
the rotation will happen. Maybe you can go from downwards to above or above to
downwards. The rotation can happen here. The third best area is the upper back
and the buttocks, which can be again rotated same ways as I explained about the
abdomen. And the last part is the upper part of the arm.
Why is rotation important in a patient? Because ijecting insulin can cause
lipodystrophy, that is the abnormal distribution of the fat. So, lipodystrophy can be
of two types. It can be lipohypertrophy, that means you will see some swelling
around the area where the patient is injecting again and again or lipoatrophy that
means you can see some absence of the fat from certain areas. Both these areas can
cause some variation in the insulin absorption. That is why the patient should
always be instructed to rotate the site whenever they inject. When using a syringe
you should always make sure patient uses the correct color code of the syringe.
So, when using a pen they should dial the desired amount of insulin, 20 in this
case, now you have the site ready, you just have to pinch it. So pinching requires
just having to use your three fingers and pinch slightly. You don't have to dig deep
and get the muscle out. You just want some subcutaneous tissue so you can inject
the insulin. Just pinch it slightly and make sure that the injection and the pen goes
straight away into 90°.
Many of your patients are on premixed insulin or NPH or a different combination.
So, whenever the patient is on a premix insulin or an NPH insulin, make sure you
tell your patient to properly mix the insulin. So if the patient is using a vial or a
syringe or a pen, the mixing has to happen properly. So whenever it is vial, you
have to just tell the patient to roll the vial in between their palms and justice rub it
for 10 to 15 times. So, this is much easier for the patients. Make sure the patients
do not shake the insulin because the shaking of the insulin will reduce the potency
of the insulin. So, whenever a patient is injecting insulin with a syringe, you should
make sure the patient uses the correct color code of the syringe. So red color code
is used for 40 international units vial, And orange color is used for 100
international unit vial.
Suppose we tell our patient to inject 20 units of insulin. The patient should retract
the plunger to 20 and push the air inside the vial. For that, you have to 1st clean it
with swab and inject 20 amount of air to make the pressure stable and then, We
have to just pull the plunger and come towards 20.
So there are some air bubbles. So, make sure that there's no air bubbles, just prime
it so there's no air bubble. Now this injection is ready to be inserted. when using a
pen, you should Dial the desired amount of insulin, say 20 in this case. Now you
have the site ready, you just have to pinch it. So pinching requires just having to
use your three fingers and pinch slightly. You don't have to dig deep and get the
muscle out. You just want some subcutaneous tissue so you can inject the insulin.
Just pinch it slightly and make sure that the injection, the pen goes Straightaway
inside at 90. °

New ADA 2022

Drug-specific and patient factors to consider when selecting

antihyperglycemic treatment in adults with type 2 diabetes.
Figure 3. ADA-recommended approach to initiating and titrating insulin in
type 2 diabetes [5]
Figure 4. Algorithm for adding/intensifying Insulin
Basal-bolus regimen
Basal insulin alone is commonly used as an initial regimen, beginning at 10 U or
0.1 to 0.2 U/kg, usually in addition with metformin or other oral agents. Basal
insulin alone is especially useful to control elevated fasting blood glucose.
Once basal insulin has been titrated to achieve the fasting blood glucose goal but
HbA1c still remains above target, then prandial insulin is added to cover
postprandial glucose excursions
Mealtime (prandial) insulin, which consists of one to three injections of a rapid
acting insulin analog* (lispro, aspart, or glulisine) or regular insulin is administered
just before eating.
As an alternative method, we can calculate the total daily dose of insulin and then
provide one half of this amount as basal and the other half as mealtime insulin,
with the latter split evenly between three meals.
As an example, if the total daily insulin requirement adds up to 60 units of insulin,
then we can give 30 Units as Lantus and 10 Units of prandial insulin, three times
daily, before each meal.

Split mixed regimen

Combination of short acting and intermediate acting (NPH) insulin is given two
times a day, before breakfast and dinner. This provides more flexibility in dose
adjustment, however also increases the complexity.

Premixed insulin therapy

Alternatively, we can consider transitioning from basal insulin to a twice daily
premixed insulin analog* (30/70 aspart mix, 25/75 or 50/50 lispro mix), if HbA1c
remains above target despite addition of insulin.
Initially we can begin by dividing total daily dose into 2/3 AM, 1/3 PM or ½ Am,
½ PM.
Once any insulin regimen is initiated, titration of dose is important, with
adjustments made in both mealtime and basal insulins to help achieve glycaemic
goals, keeping in mind the pharmacodynamic profile of each formulation used.
Comprehensive education should include self-monitoring of blood glucose, diet,
and exercise and how to respond to hypoglycaemia.

How to target hyperglycaemia during various parts of the

day?
Fasting hyperglycaemia?
Typically basal insulin like glargine, degludec, or detemir are used. For some
patients with financial issues, neutral protamine hagedorn (NPH) can be used as
first line treatment. If we use NPH as a basal insulin for overnight glucose control,
it should be administered at bedtime; if used earlier it could cause nocturnal
hypoglycaemia, or it might not last through the night and not control morning
hyperglycaemia.

Post prandial hyperglycaemia?

Rapid acting insulin or premixed insulin can be used for targeting post meal
excursions in glucose.

Other insulin choices

Premixed insulins
It consists of 50%, 70% to 75% intermediate insulin and 25%, 30% to 50% short or
rapid acting insulin. Their pharmacodynamics profiles are mentioned in table 1.
These premixed insulins can be useful in certain situations. If a patient's lifestyle
and schedule are fairly regular (including meal patterns) and do not require
flexibility, a premixed insulin may work.
Concentrated insulins
Insulin lispro is available in U-200 form which means that it has 200 units per ml
of insulin lispro. Insulin glargine is available as U-300 (300 units per ml). These
insulins are especially useful in patients who require high doses as the volume of
administered insulin is small with less glycemic variability. Also U-300 insulin
glargine has been shown to result in less nocturnal hypoglycemia compared to U-
100 glargine.

General points in initiation and continuation of insulin

 Initiation of insulin depends on the level of blood sugar, state of the patient,
various comorbidities, and ability of the patient to take orally
 When starting insulin patient must be educated regarding self monitoring of
blood glucose, and hypoglycemia
 Starting dose of insulin has been mentioned in this para. This however can
be modulated according to the factors mentioned above
 Acceleration and acceleration depends upon blood glucose level and
monitoring
 If patient is admitted for any illness and is generally stable previous insulin
dose should be continued
 If for any reason oral hypoglycemic drugs are discontinued then insulin dose
should be escalated

Future insulins
Basal insulins on the horizon
PEGylated insulin lispro long acting is an insulin analog (basal insulin analogue)
with reduced intraday variability (a very flat profile of action and a lower risk of
nocturnal hypoglycaemia) and weight loss. Pegylated insulin lispro has a Tmax
after 18 to 42 h and a T½ of 24 to 45 h compared with 10 to 12 and 12 to 15 h for
insulin glargine.
The weight sparing effect is probably a result of its hepato-selectivity leading to
less lipogenesis and increased lipid oxidation compared with insulin glargine.
Inhaled insulin
Human insulin powder for inhalation (Affreza) was approved by FDA in 2014 but
is not yet available in many countries.
Parenteral delivery is the preferred mode for most polypeptides, as oral
administration results in loss of biopotency, owing to breakdown in the stomach.
The lung provides an alternative option for therapeutic administration of
polypeptides, given its accessibility and large alveolar capillary network for drug
absorption.
Once inhaled, insulin is rapidly absorbed with its onset of action reaching a
maximum peak blood insulin concentration within 15 to 30 minutes. Inhaled
insulin is designed to be used to control postprandial glucose levels. It is
contraindicated in patients with chronic lung disease, such as asthma or chronic
obstructive pulmonary disease (COPD) and in patients who have more than six
months of smoking history and need pulmonary lung function test before starting
the treatment.

Side effects of insulin

Side effects of insulin include:
 weight gain,
 sensitivity reaction,
 hypoglycaemia and
 insulin injection site reactions which may include change in fat tissue, skin
thickening, and redness, swelling, and itching.
Frequent examination of the insulin injection site is needed by the provider to
ensure appropriate insulin delivery before adjusting the dosage.

Key points
 For patients optimized on oral agents with HbA1c greater than 8.5 %, we
suggest adding insulin.
 Insulin can be considered initial therapy with HbA1c greater than 10%, or
ketonuria.
 Initial dose of basal insulin is 0.2 Units per kg daily, subsequent titration
made to achieve fasting glucose in range 70 to 130 mg/dl.
 Patients who have achieved fasting glucose targets but still have elevated
HbA1c, are likely to require addition of prandial insulin to their basal
regimen.
 For any of the above insulin strategies, factors, such as the patient’s age,
lifestyle, competence, personal preferences, and comorbidities should be
considered when individualizing therapy.