1. ‘Glaritus’
Insulin Glargine
The True Basal 24 Hour Long Acting Insulin
Santi Syafril
Endocrine Metabolic and Diabetes Division, Internal Medicine Department,
◦ Adam Malik Hospital Medan / FK-USU
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PT
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30%
WH
Y
O
UU
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IM
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2. Diabetes Mellitus Problems in Indonesia
• Diabetes Mellitus prevalence is
increase
AMPUTASI
PENYAKIT
JANTUNG
KEBUTAAN GAGAL
GINJAL
• Glycemic target achievement is low
• Increase diabetic
complications will increase
health cost burden
4. 7
IDF Atlas 2021
Top 10 countries or territories for number of adults
(20-79 years with diabetes in 2021 and 2045
5. RISKESDAS 2018: Diabetes Prevalence
in Indonesia 10.9%1
1. Kementerian Kesehatan. Riset Kesehatan Dasar 2018.
Prevalens
i DM
menurut
Konsensu
s Perkeni
2011
pada
penduduk
umur ≥
15 tahun
0
2
4
6
8
10
12
2007
2013
2018
1.5 2.4
1.5
4.2 4.5
9.4
5.7 6.9
10.9
D-DM UD-DM T-DM
In 2018: 86%
Undiagnosed diabetic patients
7. Mayority type 2 Diabetics in Asia-Pacific
failed to achieve glycemic target (HbA1c <
7%)
Hong Kong
(Diab Registry6)
S. Korea
(KNHANES8)
43.5%
56.5%
Australia
(St
Vincent’s1)
China
(Diabcare7)
41.1%
58.9%
India
(DEDICOM4)
37
.8
62
.2
37.8%
62.2%
Thailand
(Diab Registry2)
30.2%
69.8%
Singapore
(Diabcare3)
33.0%
67.0%
39.7%
60.3%
70.0%
30.0%
HbA1c at or
below target
HbA1c above target
1.Bryant W, et al. MJA 2006;185:305–9. 2. Kosachunhanun N, et al. J Med Assoc Thai 2006;89:S66–71
3. Lee WRW, et al. Singapore Med J 2001;42:501–7. 4. Nagpal J & Bhartia A. Diabetes Care 2006;29:2341–8
5. Soewondo P, et al. Med J Indoes 2010;19:235–44. 6. Tong PCY, et al. Diab Res Clin Pract 2008;82:346–52
7. Pan C, et al. Curr Med Res Opin 2009;25:39–45. 8. Choi YJ, et al. Diabetes Care 2009;32:2016–20.
9. Mafauzy M, et al. Med J Malaysia 2011;66:175–81.
10. Jimeno CA, Sobrepena L, Mirasol R. Phil. Journal of Int Med 2012; 50 (1):15-22
22.0%
78.0%
Malaysia
(DiabCare9)
32.1%
67.9%
Indonesia
(Diabcare5)
Philippines
(DiabCare10)
85.0%
15.0%
8. Poor Glycemic Control in Type 2 Diabetics
in Indonesia
More than 70% patients in Indonesia not achieved glycemic control target
<7%
7-9.9%
>10% 28.3%
43.5%
28.2%
HbA1C Achievement
Soetedjo et al,
2018.
n=783
Soetedjo et al, Trop Med and Int Health. 2018 (23): 1118-1128
10. Prevalence of type 2 Diabetes complications
in Indonesia in 2016
Hidayat et al, Value Health Reg Issues. 2022; 28:82–89
11. Uncontrolled diabetes mellitus will increase
diabetic complications and future increase
health cost burden1
(Liebl et al. Kosten des Typ-e-Diabetes in Deutschland. DMW 2001; 126(20): 588)
Total diabetic cost depend on complication
Incrased 2.4
fold
Increased 2.5
fold
Increased 4.1
fold
Diabetes without
complication
Diabetes with
microvaskular
complications
Diabetes with
macrovaskular
complications
Diabetes with
micro and macrovaskular
complications
12. Only 1% decrease of HbA1c will decrease
long term diabetic complications1
1. Stratton IM et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS
35): prospective observational study. BMJ. 2000;321(7258):405-412.
43%
Amputation
37%
Microvaskular
complications
19%
Catarac
extraction
14%
Miokard
infarct
16%
Heart
failure
12%
Stroke
13. What is clinical inertia?
Clinical inertia may mean different things to
different people……..
In essence clinical inertia may be considered as
a delay or failure to initiate or escalate therapy
and may lead to clinical and economic
implications
14. Earlier and appropriate intervention may
improve patients’ chances of reaching goal
HbA1c, glycated haemoglobin; OAD, oral antidiabetic medication
Adapted from: Khunti K, et al. Diab Care 2013;36:3411–7; Del Prato S, et al. Int J Clin Pract 2005;59:1345–1355
HbA
1c
Time
OAD
monotherapy
OAD triple
combination
OAD dual
combination Insulin
Conventional stepwise
treatment approach
Earlier and more aggressive
intervention approach
10
9
8
7
6
8.7% 9.1% 9.7%
8.5%
For all patients
2.9 years 7.2 years 6.7 years
8.4% 8.8% 9.0%
For those with
HbA1c ≥7%
15. Insulin is the most effective choice in
decreasing blood glucose
Nathan et al., Diabetes Care 2009;32:193-203.
Decreasing HbA1c: Monotherapy potency
Early insulinization for better effectivity
16. Rationale for early initiation of insulin
1
2
3
4
5
Owens et al, Diabetes Technol Ther. 2013 Sep; 15(9): 776–785.
Overcoming the glucotoxic effects of
hyperglycemia
Facilitating “β-cell rest,” and
preserving β-cell mass and function
Improves insulin sensitivity
Long term protection to end organs
Avoid prolonged glycemic burden and
alters disease progression
52% diabetic patients
had complication at
diagnosis1
2 of 3 patients were
uncontrolled even
with treatment2
17. Time of day (hours)
400
300
200
100
0
6 6
10 14 18 22 2
Plasma
glucose
(mg/dl)
Normal
Meal Meal Meal
20
15
10
5
0
Plasma
glucose
(mmol/l)
Hyperglycaemia due to an increase in fasting glucose
T2DM
Why initiation with Basal Insulin?
Decreased (fasting/basal) blood glucose
will decreased whole blood glucose profile
24 hours1
1. Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―1239. 2. Riddle MC et al. Diabetes 2010; 59 (Suppl. 1) :A171
24% 22% 21% 21% 20%
76% 78% 79% 79% 80%
0
20
40
60
80
100
Fasting hyperglycaemia
Postprandial hyperglycaemia
In OAD therapy, fasting
hyperglycemia, contributes more
to increased HbA1C2
18. Why are Basal insulin levels so
important?
Physiological Basal insulin 0.5 – 1.0 U/Hour.
The main function of basal insulin is to
regulate basal hepatic glucose
production in the fasting state and
between meals or snacks.
REGULATES FASTING PLASMA
GLUCOSE
(Diabetes Care 2002;25:395-6.)
19. Ideal Basal Insulin
The ideal basal insulin should..…
Mimic the physiological Insulin secretion pattern
Have square-wave action profile, i.e., no peak, long-lasting
Have reproducible effects
Have pharmacodynamic effects similar to pump insulin
This need is fulfilled by:
INSULIN GLARGINE
21. Insulin glargine provides a reliable,
constant basal insulin concentration to
control basal metabolism with one injection
daily
22. Production of Glargine
Using a non pathogenic superior strain of Escherichia
coli by a Recombinant DNA technology
23. Provides
stability at
acidic pH
Shifts isoelectric
point from pH 5.4 to
6.7; Makes the
molecule soluble at
slightly acidic pH &
less soluble at
physiologic pH
Development of Glargine
(How is it different from human insulin?)
Altered pharmacokinetics of Glargine
24. Mechanism of action of Glargine
Clear Solution
pH4
Precipitation
Dissolution
Capillary Membrane
Insulin in Blood
Hexamers Dimers Monomers
24
pH 7.4
Injection of an acidic
solution (pH 4.0)
Precipitation of glargine
in subcutaneous tissue
(pH 7.4)
Slow dissolution of free
glargine hexamers from
precipitated glargine
(stabilized aggregates)
Delayed Absorption
Prolonged action
25. Drug Concentration Levels of Glargine
Glargine
• Onset of action – app 1-2 hrs
• Duration of action- 24 hours…A flat insulin profile
between 1 and 24 hours…A constant basal insulin supply
for 24 hours with no pronounced peak Peakless) …24
hour glycaemic control…can be taken at any time of the
day… Meal INDEPENDENT
• Constant release with no pronounced peak
(peakles)…Minimal hypoglycaemia
26. Achievement of Target HbA1c
Proportion Of Patients Achieving Target Hba1c <7%
N=2938
27. Reduction in Hypoglycemia
N=2938
Insulin glargine vs.
comparator in patients aged
<65 years and ≥65 years.
Conclusion:
Analysis by therapy demonstrates that insulin glargine is associated with better glycemic control
and a reduced incidence of daytime and any hypoglycemia in both younger and older T2DM
patients than comparators
Incidence of hypoglycemia
28. Variable Time of Administration
Screening phase
Week – 4 to
Week –1
Week 0
(baseline)
Week 24
(endpoint)
Titration/treatment phase
2 days
Observation
*Insulin glargine titration target: FBG 4.4-6.6 mmol/L (80-120 mg/dL) in the screening phase.
†Lispro was individually titrated and injected before or immediately after a meal.
FBG, fasting blood glucose.
Insulin glargine* prebreakfast + mealtime lispro† (n=121)
Insulin glargine* predinner + mealtime lispro† (n=128)
Insulin glargine* bedtime + mealtime lispro† (n=129)
Type 1 DM
n=378
Hamann A et al. Diabetes. 2002;51(suppl 2):A53. Abstract 215.
29. Glargine: Flexible Dosing Time
Type 1 DM
Hamann A et al. Diabetes. 2002;51(suppl 2):A53. Abstract 215.
Endpoint HbA1c
0
1
2
3
4
5
6
7
8
9
Treatment group
HbA
1c
(%)
Breakfast Dinner Bedtime
(n=121) (n=128) (n=129)
29
30. Favourable Weight Profile
Adapted from Dreyer M. Poster presented at: American Diabetes Association 62nd Scientific Sessions; June 14-18, 2002; San
Francisco, Calif.
Basal/bolus therapy with insulin Glargine:
Minimal effect on weight gain
Time (months)
30 33 Endpoint
Baseline
65
70
75
Weight
(kg)
6 18 24
Type 1 DM
30
32. What are biosimilars?
Legally approved subsequent versions of innovator
biopharmaceutical products made by a different
sponsor following patent & exclusivity expiry of the
innovator product
• Because of structural & manufacturing complexities,
these biological products are considered as similar,
but not generic equivalents of innovator
biopharmaceuticals
33. Biosimilar insulins (BIs)
BIs like Insulin Glargine are as effective and safe as the
originator insulins
Heinemann, Journal of Diabetes Science and Technology 2014, Vol. 8(1) 6– 13
34. Mean Plasma Glargine Concentration vs. Time by Formulation
Biosimilar Insulin glargine - PK
38. Switch from NPH to Glaritus
NPH once daily: Initiate glargine at same dosage;
titrate appropriately
NPH twice daily: Initiate glargine at 20% reduced dose
of total daily IU of NPH
S.N. Switch from NPH Glargine Dose
1 NPH insulin once daily 1.0 x NPH insulin dose
2 NPH insulin twice daily 0.8 x NPH insulin dose
39. Switch from Premixed to Glaritus
Premixed once daily: Initiate glargine at same dosage as
NPH; titrate appropriately
Premixed twice daily: Initiate glargine at 20% reduced
dose of total daily IU of NPH component
S.N
.
Switch from premixed Glargine Dose
1 Premixed (30/70 or 25/75) insulin OD 0.7 x Premixed insulin dose
2 Premixed (30/70 or 25/75) insulin BD 0.56 x Premixed insulin dose
3 Premixed (50/50) insulin OD 0.5 x Premixed insulin dose
4 Premixed (50/50) insulin BD 0.4 x Premixed insulin dose
40. Titrating Glaritus
Most FPG readings over past
three to seven days (mg/dl)
Insulin adjustment
>= 180 Increase by 6 units
140 to 179 Increase by 4 Units
110 to 139 Increase by 2 units
80 to 109 No change
Less than 80 Decrease
42. GLARITUS Study
Safety & Efficacy of Glaritus® Versus Lantus® in
Indian Patients with Type 1 Diabetes Mellitus
• Non-inferiority in glycemic control
Primary
Objective
• Change in blood glucose levels
• Change in glargine dose
• Immunogenic response
• Subjects with hypoglycemia episodes
• Subjects’ safety
Secondary
Objectives
Prospective Randomized Multicenter Comparative
Non-
inferiority
Open Label Parallel
N=161 (Glaritus86/Lantus 85); 14 Centers; Duration: 12 Weeks
43. Results: Efficacy
43
JAFES 2014;29(2):207
Glaritus (n=81)
Lantus (n=77)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Glaritus Lantus
0.69
0.53
Mean
decrease
in
HbA1c
levels
Decrease in HbA1c levels from baseline
P=0.454
Difference of adjusted means of change in HbA1c was 0.20 (<USFDA
specified non-inferiority margin of 0.4*)
*Ref: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071624.pdf
44. Results: Efficacy
10/3/2023
JAFES 2014;29(2):207
44
0
1
2
3
4
5
6
7
8
9
Glaritus Lantus
8.81
5.28
Mean
decrease
in
blood
glucose
levels
(mg/dL)
Decrease in blood glucose
levels from baseline
P=0.792
0
10
20
30
40
50
60
70
No Change >10% Increase >10% Decrease
69.1
23.5
7.4
63.6
27.3
9.1
Percentage
of
patients
Change in glargine dose
Patients with change in glargine dose from
baseline
P=0.5
Glaritus (n=81)
Lantus (n=77)
45. Results: Safety
10/3/2023
JAFES 2014;29(2):207
45
Parameter Glaritus (n=81) Lantus (n=77) P Value
Immunogenic
Response*
Mean ± S.D.95% C.I.
0.25 ± 0.97
-0.04, 0.37
0.02 ± 0.68
-0.18, 0.22
0.306
No. of subjects with
hypoglycemic episode
22 (27.2%) 22 (28.6%) 0.843
Adverse Events Glaritus (n=86) Lantus (n=85)
No. of Subjects 9 (10.5%) 12 (14.1%)
No. of Events 10 14
Study results are comparably similar for Glaritus and Lantus
arm
* Assessed by change in serum anti-insulin antibody (AIA) levels from baseline
46. Conclusion of this Study
10/3/2023
JAFES 2014;29(2):207
46
Glaritus® is Safe,
Effective, & Comparable
to Lantus®
47. Important Notes
Glaritus should NOT be administered
intravenously
Glaritus should NOT be mixed with any other
insulin product or diluted with any solution.
Glaritus should not be used to treat diabetic
ketoacidosis
48. Dosage In Special Populations:
Condition Glaritus Dose
Dosage in Renal Failure
No Studies conducted
The dosage of Glaritus may be
less in this population
Careful glucose monitoring is
necessary in these patients
Dosage in Hepatic Insufficiency
49. Dosage In Special Populations:
Glaritus in Pregnancy & Lactation
U.S. Food and Drug Administration's Pregnancy
Category: Category C (All Trimesters)
Drugs should be given only if the potential benefit justifies the
potential risk to the fetus.
Infant risk cannot be ruled out
50. Dosage In Special Populations
Paediatric population
Insulin glargine may be used for children who are 6
years or older
It has NOT been studied in children younger than 6
years of age.
50
51. Say YES to Control…… With GLARITUS
ONE shot a day
No worries about Meal timings
Minimal Hypoglycaemia
LIFESTYLE FLEXIBILITY…
52. Pasien diabetes melitus tipe 2
1
Belum terkontrol dengan
kombinasi metformin dosis optimal & OAD lain
HbA1c > 7.5%
Rerata gula darah 169 mg/dl
Pasien diabetes melitus tipe 2
2
HbA1c > 9%
Gejala dekompensasi metabolik
Pemberian insulin pada (1) dan (2) dapat dilanjutkan untuk pasien diabetes melitus tipe 2, jika insulin
dibutuhkan untuk mempertahankan pengendalian glukosa darah.
3
Inisiasi insulin basal dan premix
FORNAS terbaru berlaku 1 Januari 2022
UPDATE
TERBARU!
53. Dalam FORNAS terbaru,
disebutkan bahwa Dokter di
Faskes Tk.1 dapat melakukan
penyesuaian dosis hingga 20
IU/hari.
Penyesuaian dosis insulin hingga 20 IU/hari oleh
Dokter FKTP
FORNAS terbaru berlaku 1 Januari 2022
KMK No.HK 01.07/MENKES/6485/2021 tentang Formularium Nasional
54. Summary
Clinical inertia is a real issue, with hypoglycaemia a
major barrier to glycaemic goal achievement
Treatment paradigms in diabetes are shifting toward
earlier intervention
Insulin represents a therapeutic mainstay
On-going developments in insulin pharmacology aimed at
optimising the use of exogenous insulin in clinical
practice
