basal insulin in diabetes management

1. Basal Insulin- A
breakthrough in Insulin
Therapy Dr. Pranab Kumar Sahana
Associate Professor
Department of Endocrinology
NilRatan Sircar Medical College
Kolkata

2. First Human Patient
On Jan. 11, 1922, 14-year-old Leonard Thompson
was the first human patient to receive insulin
made by Banting and Best.
Leonard's blood glucose dropped to normal, and
he began to gain weight.

3. Human insulin molecule

4. Normal Pancreatic Function
Meal Meal Meal
Prandial: At mealtime,
insulin is rapidly released
in response to food.
Basal: Beta cells secrete
small amounts of insulin
throughout the day.
Basal Insulin
Bolus Insulin
*Insulin effect images are theoretical representations and are not derived from clinical trial data.

5. Short Comings on Animal
Insulins
• Impurity
• Antigenecity
• Allergic reaction

6. Shortfalls of Regular Human Insulin (1978)
• Short acting in nature( 6-8 hours).
• Multiple daily injections to match physiological release
pattern.
• Less treatment satisfaction.
• Unpredictable Hypoglycemia

7. Concept of Basal Insulin

8. Neutral Protamine Hagedorn
(1940-50)
• Hans Christian Hagedorn in 1936 added
protamine from trout semen to insulin.
• Protamine is a highly bsaic protein
• Later Zinc was added to stabilize the complex
• Leads to microprecipitation and delayed
absorption and prolonged duration of action
• 1950 Nordisk markets NPH Insulin

9. NPH suspension at room
temperatre

10. Rationality of Basal Insulin
• Basal insulin supresses hepatic glucose
output and also lipolysis between meals
and in night
• Prevents Ketoacidosis in Type 1
• Most individuals with type 2 diabetes will
achieve adequate glycemic control with
the addition of basal insulin alone
ADA/EASD 2015, IDF, NICE 2014

11. Benefits of NPH Insulin
• Effective
• Useful in Dawn phenomenon
• Safe in pregnancy, children

12. Limitations of NPH
Do not mimic basal insulin profile
– Variable absorption and action
– Pronounced peaks
– Action profile depends on dose
– Risk of nocturnal and unpredictable hypoglycemia
– Less than 24-hour duration of action
– More weight gain

13. Ideal Basal Insulin
13
• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect around 24 hours
• Smooth, peak less profile
• Reproducible and predictable effects
• Reduced risk of nocturnal hypoglycaemia & weight gain
• Once-daily administration for convenience
• Flexible meal timings
Hawkins M, et al. Joslin's Diabetes mellitus. 14th Edition. Lippincott Williams and Wilkins. 2000:426–448

14. Insulin Glargine (2000)
• Modifications to human insulin chain
– Substitution of glycine at position A21
– Addition of 2 arginines at position B30
• Gradual release pattern from injection site
• Peakless, long-lasting insulin profile
1 5 10 15 20 25 30
1 5 10 15 20Asp
Gly
Arg
Extension
Substitution
Arg

15. 15
Clear
solution
pH 4.0
S.C. Injection of
an acidic solution (pH 4.0)
Glargine: First 24-h
rDNA basal insulin
analogue in clinical
practice
Capillary Membrane
Insulin in Blood
Dissolution
Hexamers Dimers Monomers
10-3
M 10-5
M 10-8
M
Slow dissolution of free
glargine hexamers from
precipitated Glargine
Protracted action
Insulin Glargine
1) McKeage K et al. Drugs. 2001;61:1599-1624, 2) Campbell RK et al Clin Ther. 2001; 23(12):1938-1957, 3) Wang F et al Clin Ther. 2003;25:1541-1577.

16. Once-daily insulin Glargine has consistently demonstrated
efficacy in helping type 2 diabetes patients achieve target
glycaemic control
EASIE9
(n=480)
24 weeks
TULIP1
(n=211)
36 weeks
INSIGHT2
(n=405)
24 weeks
TTT3
(n=764)
24 weeks
APOLLO4
(n=412)
44 weeks
LAPTOP5
(n=364)
24 weeks
TRIPLE6
(n=216)
24 weeks
LANMET7
(n=110)
36 weeks
L2T38
(n=973)
24 weeks
In clinical efficacy studies using a target FPG <5.6 mmol/L and comparing Glargine® /OADs vs. different comparators, T2DM patients were
well controlled on Lantus® treatment with a low rate of hypoglycaemia and well-characterised adverse event profile
T2DM
Baseline HbA1c
Endpoint HbA1c
1. Blicklé JF, et al. Diabetes Obes Metab 2009;11:379-386
2. Gerstein HC, et al. Diabetes Med 2006;23:736-742
3. Riddle MC, et al. Diabetes Care 2003;26:3080-3086
4. Bretzel RG, et al. Lancet 2008;371:1073-1084
5. Janka HU, et al. Diabetes Care 2005;28:254-259
6. Rosenstock J, et al. Diabetes Care 2006;29:554-549
7. Yki-Järvinen H, et al. Diabetologia 2006;49:442-451
8. Swinnen SG, et al. Diabetes Care 2010;33:1176-1178
9. Aschner P, et al. Lancet 2012;379:2262-2269
BOT, basal insulin-supported oral therapy
OAD, oral antidiabetic drugs
Consistent achievement of HbA1c targets (or close to it)
when Glargine was added to type 2 patients uncontrolled
on OAD treatment (BOT regimens)

17. HbA1c reductions with once-daily insulin Glargine in controlled
trials of varying duration and size in type 1 diabetes
1. Raskin P, et al. Diabetes Care 2000;23:1666-1671
2. Bolli GB, et al. Nutr Metab Cardiovasc Dis 2009;19:571-579
3. Fulcher GR, et al. Intern Med J. 2005;35:536-542
4. Ashwell SG, et al. Diabet Med 2006;23:285-292
5. Chatterjee S, et al. Diabetes Res Clin Pract 2007;77:215-222
6. Porcellati F, et al. Diabet Med 2004;21:1213-1220
T1DM
Raskin
(2000)1
(n=619)
16 weeks
Bolli
(2009)2
(n=175)
30 weeks
Fulcher
(2005)3
(n=125)
30 weeks
Ashwell
(2006)4
(n=56)
32 weeks
Chatterjee
(2007)5
(n=53)
36 weeks
Porcellati
(2004)6
(n=121)
52 weeks
Baseline HbA1c
Endpoint HbA1c
Once-daily Glargine has demonstrated effective
HbA1c reductions across a wide range of randomised
controlled trials in type 1 diabetes

18. Hypoglycemia defined as plasma glucose ≤72 mg/dL
*P<0.05 vs insulin glargine.
NPH=neutral protamine Hagedorn
Adapted from Riddle M et al. Diabetes Care. 2003;26:3080-3086. Used with permission.
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
20 22 24 2 4 6 8 10 12 14 16 18
Time of day (h)
*
*
*
*
*
*
*
Glargine
NPH
Basal
insulin
Breakfast Lunch Dinner
Eventsperpatientexposure–year
Symptomatic Hypoglycemic Events

19. 19
Limitations of Insulin Glargine
• It can not be mixed with other short/rapid acting insulins
as the pH of the formulation is acidic.
• Initially it may produce burning sensation due to acidic
pH.
ADA Practical Insulin: A handbook for prescribing providers. 3rd
ed., Heise T et al. Diabetes 2004; 53(6): 1614-1620

20. Thr
Glu
Lys
ValPhe
Asn
Glu
Leu
Gln
Tyr
Leu
SerCysIleSerCys
Cys
Gln
Glu
Val
Ile
Gly
Tyr
CysAsn
Lys
Pro
Thr
Tyr
Phe
Phe
ArgGly
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Asn Gln
Leu
HisB1
A21
A1
B29
C14 fatty acid chain
(Myristic acid)
Thr
Detemir Properties:
 Neutral pH
 Long extended action
 More within patient
consistency
 Less hypoglycemia
 Less weight gain
Insulin Detemir (2004)

21. Insulin detemir versus insulin glargine for type 2
diabetes mellitus.
Swinnen SG1
, Simon AC, Holleman F, Hoekstra
JB, Devries JH.
• there is no clinically relevant difference in efficacy or
safety between insulin detemir and insulin glargine
for targeting hyperglycaemia. However, to achieve
the same glycaemic control insulin detemir was often
injected twice-daily in a higher dose but with less
weight gain, while insulin glargine was injected once-
daily, with somewhat fewer injection site reactions.
Cochrane Database Syst Rev. 2011 Jul 6;(7)

22. Insulin degludec (2013)
Rationally designed, beyond sequence modification
Jonassen I et al. Pharm Res 2012;29:2104–2114.
N
H
O
OH
O NH
O
OH
O
DesB30 insulin
DesB30
T
Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin
s
s
s
s
A1
B1
A21
s s
L-γ-Glu
Glutamic acid
‘spacer’
N
H
O
OH
O NH
O
Hexadecandioyl
Fatty diacid side
chain

23. Degludec : Mode of Action of
(Retarded Absorption)
Insulin degludec for injection is a
zinc/phenol formulation in the T3R3
conformation as di-hexamers (~69 kDa)
Zinc diffuses slowly causing
individual hexamers to disassemble,
releasing dimers and then monomers
Monomers are absorbed from
the depot into the circulation
- Phenol
Monomers bound to albumin
(protein-bound depot)
Rapid phenol depletion (after injection)
changes the conforation to a T6-state
exposing the core and Zinc ions and
multi-hexamer chains are formed
- Zinc
multi-hexamer chains

24. Flexible Dosing Schedule of Degludec
morning
Mon Tue Wed Thu Fri Sat Sun
morning morning
evening evening evening evening
40h 40h 40h
8h 8h
24h
Dosing schedule provided for a maximum dosing
interval of 40 hrs & a minimum doisng interval of 8
hrs.
Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423;
Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

26. Pharmacokinetics of Basal Insulin
ONSET PEAK DURATION variability
NPH 2-3 hours 6-8 hours 13-16 hours 68%
DETEMIR 2-3 hours 6-8 hours 12-18 hours 27%
GLARGINE 2-3 hours No peak 24 hours 32-82%
DEGLUDEC 2-3 hours No peak 42 hours 20
GLA 300 2-3 hours No peak >24 hours 17-35
Peg- Lispro 2-3 hours No peak >24 hours 18

27. Insulin Glargine vs. Insulin Detemir
vs. NPH insulin
Aspects Parameters
Insulin
Glargine
Insulin
Detemir
NPH
Insulin
Efficacy & Safety
FPG reduction - - -
HbA1c reduction - - -
Hypoglycaemia + + ++
Weight gain + neutral ++
Long term
efficacy
+ + +
Pharmacoeconomics Cost of therapy ++ +++ +
27
1) Hedrington MS, et al. Diabetes Technol Ther. 2011;13(Suppl 1):S33-42, 2) Pfohl M et al., Health Outcomes Research in Medicine. 2011;2(1):e39-e50

28. SWITCH – trial design
IDeg, insulin degludec; Iglar (U100); NN Trial ID NN1250-3998 and 3995
Trial information
•Double-blind
•Cross-over
•Treat-to-target
•Randomised 1:1and
50/50 AM/PMMaintenance
phase
16 weeks
Maintenance
phase
16 weeks
IGlar OD ± OADs
IDeg OD ± OADs
Titration
phase
16 weeks
IGlar OD ± OADs
IDeg OD ± OADs
Titration
phase
16 weeks
Treatment period 1 Treatment period 2
721 patients
•Age ≥18 years
•T2D ≥26 weeks
•Basal insulin ± OADs
•HbA1c ≤9.5%
•BMI ≤45 kg/m2
To reduce the risk of hypoglycaemia in the
first treatment month, the overall daily
dose of basal insulin was reduced by 20%
at randomisation for subjects treated
with pre-trial BID basal insulin.
Trial information
•Double-blind
•Cross-over
•Treat-to-target
•Randomised 1:1and
50/50 AM/PMMaintenance
period
16 weeks
Maintenance
period
16 weeks
IGlar U100 OD ± IAsp
IDeg OD ± IAsp
Titration
period
16 weeks
IGlar U100 OD ± IAsp
IDeg OD + IAsp
Titration
period
16 weeks
Treatment period 1 Treatment period 2
Basal titration (IDeg and IGlar U100)
•Once-weekly titration based on lowest of 3 consecutive days
•Target: 4.0–5.0 mmol/L (71–90 mg/dL) measurements
• 20% dose reduction at randomisation
and at switch for all patients
SWITCH2SWITCH1

29. Non inferiority in HbA1c over timeIDeg
IGlar U100
Titration period 1 Maintenance period 1 Titration period 2 Maintenance period 2
Treatment period 1 Treatment period 2
0.0 0.0
Estimated treatment difference:
0.09% [95% CI -0.04;0.23]
Non-inferiority confirmed
032
CROSS-OVER
Mean±SEM; FAS; Observed data; NN1250-3998 and NN1250-3995; Cross-over IDeg vs IGlar U100 in T2DM and T1DM
SWITCH2SWITCH1
Estimated treatment difference:
0.03% [95% CI -0.10;0.15]
Non-inferiority confirmed
Estimated treatment difference:
0.11% [95% CI -0.00;0.23]
Non-inferiority confirmed
0.0 0.0

30. IDeg
IGlar
0.5
0.0
0.9
0.7
0.4
0.1
0.8
0.6
0.3
0.2
3216 20 24 3018 22 26 28
Time (weeks)*
30% lower
with IDeg
(significant)
IDeg: 186 events/100 PYE
IGlar: 265 events/100 PYE
IDeg
IGlar
4.5
0.0
8.1
6.3
3.6
0.9
7.2
5.4
2.7
1.8
3216 20 24 3018 22 26 28
Time (weeks)*
11% lower
with IDeg
(significant)
IDeg: 2201 events/100 PYE
IGlar: 2463 events/100 PYE
Severe or BG confirmed symptomatic
hypoglycaemia – maintenance phase (rates)
T2DM
T1DM
*Combined maintenance phases of treatment period 1 and 2 (week
16-32 and 48-64)
PYE, patient-years of exposure; *Combined maintenance phases of
treatment period 1 and 2 (week 16-32 and 48-64)
IDeg IGlar U100
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
22.5% 185.6 31.6% 265.4
IDeg IGlar U100
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
77.3% 2200.9 79.9% 2462.7
p<0.0001
p<0.0001

31. IDeg
IGlar
0.16
0.00
0.32
0.24
0.12
0.04
0.28
0.20
0.08
3216 20 24 3018 22 26 28
Time (weeks)*
42%
lower
with IDeg
(significant)
IDeg: 55 events/100 PYE
IGlar: 94 events/100 PYE
IDeg
IGlar
0.6
0.0
1.1
0.9
0.4
0.1
1.0
0.7
0.3
0.8
0.5
0.2
3216 20 24 3018 22 26 28
Time (weeks)*
36% lower
rate with IDeg
(significant)
IDeg: 277 events/100 PYE
IGlar: 429 events/100 PYE
Severe or BG confirmed symptomatic
nocturnal hypoglycaemia –maintenance phase
*Combined maintenance phases of treatment period 1 and 2
(week 16-32 and 48-64)
*Combined maintenance phases of treatment period 1 and 2
(week 16-32 and 48-64)
T2DM T1DM
IDeg IGlar U100
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
9.7% 55.2 14.7% 93.6
IDeg IGlar U100
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
Proportio
n
(%
patients)
Rate
(episodes/
100 PYE)
32.8% 277.1 43.1% 428.6
p<0.0001 p<0.0001

32. Glargine U300
• New Insulin Glargine 300 Units/mL Versus
Glargine 100 Units/mL in People With Type 2
Diabetes Using Basal and Mealtime Insulin:
Glucose Control and Hypoglycemia in a 6-
Month Randomized Controlled Trial (EDITION
Diabetes Care 2014 Oct; 37(10): 2755-2762.

33. Glycemic efficacy of Glarine U300- EDITION 1
Matthew C. Riddle et al. Dia Care 2014;37:2755-2762
©2014 by American Diabetes Association

34. Hypoglycemia risk in U300 Glargine in EDITITION
1 Trial
Matthew C. Riddle et al. Dia Care 2014;37:2755-2762
©2014 by American Diabetes Association

36. Continuing innovation with new basal insulin-
longer half life and lower variability
NPH, neutral protamine Hagedorn. Kalra. J Pak Med Assoc 2013;63:1442–4; Insulatard SmPC: http://www.medicines.org.uk/emc/medicine/3512/SPC/Insulatard+100+IU+ml,+Insulatard+Penfill+100+IU+ml,+Insulatard+InnoLet+100+IU+ml#
PHARMACOLOGICAL_PROPS; Toujeo SmPC: https://www.medicines.org.uk/emc/medicine/30586#PHARMACOLOGICAL_PROPS (All accessed September 2016)
Animal
insulin
preparations
Basal insulin
analogues
Isolation of insulin
(Banting & Best)
Ultra-long-acting basal
insulin
analogues
NPH insulin
HighHigh
Half life (hours):
Variability: MediumMedium LowLow
λλ 5–105–10 12.512.5 252518–1918–19
Insulin glargine
U300
Insulin detemir Insulin degludec
Insulin glargine
U100

37. Summary
• long-acting insulin analogs (insulin glargine and insulin detemir) are not
superior to NPH insulin in efficacy terms as determined by the number of
participants reaching HbA1c targets.
• Compared with use of NPH insulin, the use of the standard long-acting
insulin analogs with relatively flat action profiles is associated with up to a
50% reduced risk of nocturnal hypoglycemia.
• Basal insulin is now the cornerstone of insulin regime in Diabetes.
• It is convenient, effective ,less hypoglycemia.
• Glargine for all practical purposess is the gold standard basal insulin.
• Frequent monitoring, patient education is also integral part.
• Proper injection technique should be taught.
• Basal insulin have to supplemented with prandial insulin in Type 1 DM and
selected cases of Type T2 DM.
• In pregnancy, NPH and Detemir are recommended basal insulins.