Module Organized by

Indonesian Society of Endocrinology

Insulin Initiation
How to Prudently Use Basal
and Prandial Insulin
with Confidence

Nanang Miftah Fajari

ID-LAN-2023-05-H4PY (05/23)
LEARNING OBJECTIVES

1. Insulin Deficiency and Increased Counter-regulatory Hormones

2. Road Map Using Insulin in out patients setting
3. Clinical Experience & Guideline: Switching to and from Ultra-Long
Acting Basal Insulin
4. Controlling PPG in a Fast and Flexible Way Using Prandial Insulin
 Absolute or Relative Insulin Deficiency and
Increased Counter-regulatory Hormones

Free Fatty Acids Amino Acids ↑ Protein

↑ Lipolysis Breakdown
Glycerol Lactate
Adipose Tissue Liver Muscle
↑ Glucose Output
↑ Glycogenosis
↓ Glucose
IV dextrose Utilization
Glucocorticoids HYPERGLICAEMIA
Catechlolamines
Inflammatory cytokines
Parenteral Nutrition Tissue Injury
Circulatory & Electrolytes Effects Reduced nitric oxide
Enteral Nutrition Volume Depletion Superoxide generation
Hypoperfusion Endothelial dysfunction
Electrolyte Loss Platelet activation
Acid Base Disturbances Immune dysregulation
Mitochondrial injury

Schönenberger et al. Management of Hyperglycemia. 2022 Sepsis, multiple organ failure & death 3
Melo FKS .Diabetol Metab Syndrome.2019
 Road Map Using Insulin in out-patients setting:
Start with Basal Insulin

1 2 3DIAGNOSE INITIATION TITRATION

4 5
Mehta R et.al. Annal Medicine.2021

GOAL
END BASAL INSULIN
TITRATION 4
 Basal Insulin is Essential
Basal Insulin
Basal Insulin has
become a mainstay in For the
Development

1
Diabetes Care maintenance of Focus
fasting Glucose Long-Acting Formulation
level

2
Flat profile of Action

Provide Minimal day to day

consistent variability
insulin levels Lower Risk of Hypoglycemia
between meals.
A predictable glucose-lowering
action from injection to injection
NPH Determir
Basal Glargine A low injection frequency
requirement ( 1x/day)
Insulin Glargine Degludec U-300
Flexibility time injection
U-100 U-100/200
5
Hirch IB. Endocrine Reviews 41: 733 – 755, 2020; Buse BJ et al .Diab Res Care 2021.
 Gla-300 vs Gla-100 : Compact depot formation results in more
gradual insulin release with Gla-300

Gla-300
300 Units/mL

Reduction of
volume by 2/3

Insulin glargine
More compact More gradual
Smaller
SC depot with and slower
volume of
smaller release from
injection1 surface area1,2 depot surface1-4

Gla-100
100 Units/mL

For illustrative purposes only

6
1. Pettus J et al. Diabetes Metab Res Rev. 2016;32:478-96; 2. Adapted from Sutton G et al. Expert Opin Biol Ther. 2014;14:1849-60;
3. Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; 4. Becker RH et al. Diabetes Care. 2015;38:637-43
 People with type 2 diabetes who are
candidates for basal insulin

HbA1c >7.0% (both Patient taking Patients taking a End-organ

those presenting well maximally tolerated prolonged course of failure; acute
above target [≥8.5%] non-insulin agents and steroids illness
but also persistently HbA1c still above target
above target over
time)

Intolerance to multiple Patients with decompensation Patients who are

non-insulin agents and severe hyperglycemia currently or wishing to
become pregnant 7
Mehta R et.al. Annal Medicine.2021
 Patients Who May Require Glargine-U300

Patients with inherited Diabetes

insulin receptor
patients with Obstetrics
abnormalities or presence
of autoantibodies to insulin patients
insulin receptor antibodies
Patients Other
With Insulin
Resistance Patients Patients receiving
Overweight/obese high-dose
Type 2 glucocorticoid
Type 1 diabetes
patients diabetes therapy
patients
8
Alan Garber. Endocrine Practice ; 2016
 Gla-100 & Gla-300 in pregnancy: No specific adverse events or congenital
abnormalities observed with Gla-300 use during pregnancy

The safety of Gla-100 & Gla-300 use during pregnancy was examined CONCLUSION
using post-marketing pharmacovigilance data
• PV data show that use of Gla-100 or Gla-300
during pregnancy was not associated with specific
adverse events or congenital abnormalities

Cases from 71 countries for Gla-100 & 44 countries for

Gla-300 • The results indicate no safety issues with insulin
glargine use during pregnancy
4936 exposures to Gla-100 & 246 exposures to Gla-300
during pregnancy

Product Information of Gla-300, BPOM 2021

Reporting rate for pregnancy/lactation-related cases was
56 per 1 million for Gla-100 & 31.1 per 1 million Gla-300 ……, A large amount of data on pregnant women (more than 1,000
patient-years pregnancy outcomes with a medicinal product containing insulin
glargine 100 units/ml) indicate no specific adverse effects on
pregnancy and no specifics malformative nor feto/neonatal toxicity
Rates of spontaneous abortions and congenital of insulin glargine
anomalies were low and consistent with the
general population Animal data do not indicate reproductive toxicity. The use of Gla-300
may be considered during pregnancy, if clinically needed.
Gla-300, insulin glargine 300 U/mL
Westerbacka J, et al. Presented at ADA 2022. June 3–7, 2022, New Orleans, LA; Lantus XR Product Information Approved BPOM 5 Feb 2021
9
Algoritma terapi insulin:
Pasien DM Tipe 2 + OHO (mono/dual/tripel) dengan HbA1c
>7,5%

INISIASI + OPIMALISASI

CO-FORMULATION
PREMIXED OD
BASAL INSULIN Atau
(sebelum makan malam)
FIXED-RATIO COMBINATION

Dosis 10 U/hari
malam hari atau 0,2
U/kg BB

OPTIMALISASI
DOSIS
Dosis maksimal 0,5
U/kgBB
INTEN SIFIKASI
 Algoritma terapi insulin:
Pasien DM Tipe 2 baru + HbA1c >9% atau GDP >250 mg/dL atau GDS >300 mg/dL, diserta gejala
dekompensasi metabolic*

FIX-RATIO COMBINATION BASAL-BOLUS

CO-FORMULATION BASAL-PLUS
Insulin + GLP1-RA
Tambahkan insulin prandial Tambahkan insulin prandial
pada makan terbesar pada ketiga jadwal makan
IDegAspart IDegLira/IGlarLixi Insulin basal malam hari Insulin basal malam hari

Mulai dosis 4 U/hari Basal: 10U malam

atau 10% dosis Prandial: 4 U atau 0,1
insulin basal U/kgBB tiap sebelum
makan

OPTIMALISASI DOSIS OPTIMASI DOSIS

OD → BID OD → BID OPTIMASI DOSIS OPTIMASI DOSIS

DEEKSKALASI

INTENS IFIKAS I
internal use 12
• NEW RECOMMENDATIONS :

1. For ultra-long-acting insulin, either glargine U-300 or degludec U-100 can be considered to be initiated first, depending on
availability, acceptability, and affordability

2. If both ultra-long-acting and long-acting insulin regimens are available, ultra-long-acting insulins (glargine U-300 and
degludec U-100)at bedtime injection should be considered to be initiated first depending on acceptability and affordability.

3. The initial dose can be considered from 0.10 to 0.20 U/kg/day for any of five basal insulins. For people with impaired kidney
function or renal insufficiency, and elderly people over 65 years, dosage for any basal insulin should be reduced as
appropriate

4. The maintenance dose can be considered from 0.3 to 0.5 U/kg/day for any of the five basal insulin regimens. In clinical
practice, clinicians and patients should use independent medical judgment in the context of individual clinical circumstances

5. The range of controlled FPG of 3.9–6.1 mmol/L (70–110 mg/dL) can be considered for any of the five basal insulin regimens
to achieve the ideal HbA1c

internal use 13
 Gla-300 associated with similar glycemic improvements and less weight gain &
Hypo incidence vs premix IDeg/Asp : Results from an ITC

• There was no significant difference in change in HbA1c or final insulin dose, although Gla-300 QD had significantly less weight
gain than IDeg/Asp QD

Treatment difference
Key outcomes Gla-300 vs IDeg/Asp
(95% CI)

0.10 (−0.20, 0.39)

Change in HbA1c, %
HbA1c p=0.5

0.03 (−0.05, 0.12)

Final insulin dose, U/kg p=0.4

−1.31 (−1.97, −0.65)

Weight gain, kg p=0.0001

• Compared with premix IDeg/Asp, Gla-300 QD showed lower incidence of any 24-h hypoglycemia and 24-h confirmed
(PG <3.0–3.1 mmol/L) hypoglycemia
• No significant differences were observed in hypoglycemia event rates
*Statistical significance
CI, confidence interval; Gla-300, insulin glargine 300 U/mL; IDeg/Asp, premixed insulin degludec and insulin aspart; ITC, indirect treatment comparison; OR; odds ratio; RR, risk ratio
Zheng L et al. Presented at ATTD 2022; 27‒30 April 2022:P#753
 Gla-300 associated with a lower risk of anytime and 24-h confirmed (PG <3.0–3.1
mmol/L) hypoglycemia compared with premixed insulin: Results from an ITC

• Gla-300 OD had lower incidence of any hypoglycaemia and confirmed (PG <3.0–3.1 mmol/L) any time (24 h) hypoglycaemia
• Gla-300 also had significantly lower event rate of any hypoglycaemia and confirmed (PG <3.9 mmol/L) anytime hypoglycaemia
• No differences were observed for either severe or nocturnal hypoglycaemia

Incidence Event Rate

*Statistical significance
CI, confidence interval; Gla-300, insulin glargine 300 U/mL; ITC, indirect treatment comparison; OR; odds ratio; RR, risk ratio
Malik R et al. Presented at IDF 2021; 06‒11 December 2021
 Initiation
NPH Glargine Detemir Gla U-300 Deg

 0.1 units/kg daily If any of: 0.2 unit/kg, 10 unit,

• HbA1c < 64 mmol/mol once daily once daily
• BMI < 18 kg/m2 (less likely to have type 2
diabetes) AACE ADA
• Older (e.g. aged > 65 years) or frailty
• Renal or liver failure A1C < 8%: 0.1-0.2 unit/kg 10 unit/d
 0.2 units/kg daily If HbA1c > 64 mmol/mol A1C > 8%: 0.2-0.3 unit/kg or
0.1-0.2 unit/kg
and BMI > 18 kg/m2

 Once daily injections at night:  Once daily injections in the morning:

 With high blood glucose levels in the
morning
 At lower risk of nocturnal hypoglycaemia
 Who can respond to a nocturnal
hypoglycaemic event, e.g. have no mobility
issues or can rely on assistance from others
Schönenberger et al. Management of Hyperglycemia. 2022
 Blood glucose levels that increase
throughout the day
 Increased risk of nocturnal hypoglycaemia
 Increased risk of consequences of a
nocturnal hypoglycaemia event, e.g. living
alone, frailty, risk of falls
16
 Titration: Adjustments Dose for Basal Insulin

Insulin Glargine
100 U/mL
Adjustment should be made according to
blood glucose measurements
Insulin Determir

3 to 4 days between dose increases. Decrease

Insulin Glargine 2 units if below FPG goal, 0 units if within FPG
300 U/mL goal, and increase 2 units if above FPG goal

Insulin Degludec
Adjust and titrate over 3 to 4 days. Should be
100 U/mL or 200
U/mL individualized to patient needs and FPG goals

17
Bhawna et al. Diabetes Ther. 2020
Titration: Road Map Using Insulin

5-15% or 1-4 units

0.1-0.2 units/kg/day
2 units
Max : 0.5 for A1C<8%.
units/kg/day
0.2-0.3 units/kg/day
<115
for A1C>8%
80-130

18
Basal Insulin Titration from World Medical Societies

1U setiap 1 hari

Target FBG mg/dL 72-126

2U setiap 3 hari Target HbA1c% ≤ 7.0
Target FBG mg/dL 70-130
Target HbA1c% < 7.0
19
 Clinical Experience & Guideline: Switching to
and from Ultra-Long Acting Basal Insulin

Reasons for Switching to iGlar U300

n=1
Improved ease Flexibility Adverse
Improve time n=10
of (e.g. for shift events or
in range
administration workers) hypoglycemic
(e.g. syringe to episodes on n=23
pen) current n=50
therapy

Hypoglicemia risk
Uncontrolled blood glucose levels
Increased insulin requirement
Simplify the insulin regimen and increase patient compliance

Change in Patient Hospitalization

insurance requires high when current insulin
coverage doses of insulin is not on the
hospital formulary

20
1. Mehta R et.al. Annal Medicine.2021; 2. Garber AJ. Endocrine Practice 2016
 Panel Recommendations for Medical Follow-
up with Diabetes HCPs
When initiating insulin or titration. Support insulin initiation and
24–72 h
reinforce titration

1–2 week(s) Patients report BG readings. Ensure titration is occurring normally

Patients report BG readings. Ensure titration is occurring normally

1 month
(it is encouraged to continue with biweekly contacts thereafter)

A1C measurement. If not at goal, patient may continue

3 months
with titration for another 3 months. Need virtual consult

A1C measurement Follow-up of titration. If A1C above target, review glycemic profile
6 months
and consider adding mealtime insulin

Within 24 h of
Educate patient on recognizing, preventing, and treating hypoglycemia
hypoglycemia
21
Bhawna et al. Diabetes Ther. 2020
Controlling PPG in a
Fast and Flexible Way
Using Prandial
Insulin

22
 Glucose metabolism in the postprandial and
post absorptive state

23
Melo FKS .Diabetol Metab Syndrome.2019
 Post Prandial insulin & Plasma Glucose profile

Postprandial Insulin Profile

Continuous glucose monitoring (CGM) studies have

shown that postprandial glucose
levels peak at a mean of 70–80 min after eating
in people with diabetes

24
Robbert. Diabetes. 2019
 Glulisine Gives Effect Faster than Aspart
A multinational, randomized, double-blind, two-way crossover trial comparing the PK and PD characteristics of glulisine & aspart in insulin-
naÏve, obese subjects with type 2 diabetes, n=30 patients with T2DM

Lower blood glucose is shown faster in glulisine group Glulisine insulin concentration is higher than
rather than aspart group during the first hour aspart

Bolli GB, et al. Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart
prior to a standard meal in obese subjects with type 2 diabetes. Diabetes Obes Metab 2011;13:251-257.
 Flexibility Usage of Glulisine :
Postprandial vs Prepandial administration
multicenter, randomized, open-label trial conducted in USA, 345 patients, for a 52-week treatment period

premeal arm: insulin glulisine 3x/day ,0–15 min before 3 main meals + insulin glargine once daily ±metformin
postmeal arm: insulin glulisine 3x/day, 20 min after the start of ameal +insulin glargine once daily, ±metformin.

Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial
administration showing dosing flexibility and the feasibility of such approach when clinically indicated.

Ratner R, et al. Diabetes Obes Metab. 2011;13(12):1142-1148.

THANK YOU 28