Diabetes Management with Basal Insulin

Dr Sultan Ahmad Mubashir

Consultant Physician
Global Diabetes Prevalence

IDF Diabetes Atlas 7th Edition

Complications related to uncontrolled
type 2 diabetes
Eyes Brain and cerebral circulation
(retinopathy, (stroke, TIA)
glaucoma, cataracts) Heart and coronary circulation
(angina, MI, CHF)
Kidneys
(nephropathy, ESRD)

Peripheral
nervous system Peripheral vascular tree
(peripheral neuropathy) (peripheral vascular disease,
gangrene, amputation)

CHF, congestive heart failure; ESRD, end-stage renal disease; MI, myocardial infarction; TIA, transient ischaemic attack
Adapted from Diabetes Atlas. 5th ed. International Diabetes Federation. 2012
 4

Eight core defects of type 2 diabetes

UKPDS: Stringent Glycaemic Control Reduces Complications

Stratton IM et al. UKPDS 35. BMJ 2000; 321:405 - 412

Exogenous Insulin Therapy:
Insulin Replacement Therapy Becomes Necessary Because of Progressive Nature of Disease

350

Glucose (mg/dL)
Prediabetes/ Diabetes Uncontrolled
300 Metabolic syndrome diagnosis hyperglycaemia
250

200 Post-meal glucose

150 Fasting glucose

Normal
100
50

250 Insulin resistance

Relative Function

200

150
Insulin level Beta-cell failure
-cell mass
100 Normal
50 Incretin effect
0
-15 -10 -5 0 5 10 15 20 25 30
Onset of Years
diabetes

Kendall DM, et al. Am J Med. 2009;122(Suppl 6):S37-S50.

Type 2 diabetes treatment efficacy: insulin is
very effective
DPP-4ia
Glinides

AGI
GLP-1 RAb

TZDs

SUs

Insulin

Metformin

Lifestyle

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Range of HbA1c reduction as a monotherapy

aAdapted to include sitagliptin and saxagliptin; badapted to include exenatide and liraglutideAGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl
peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione
Campbell et al. J Fam Practice 2010;59:S5–9
 25 March 2016 8

Clinical inertia: patient and physician barriers

Lack of appropriate Complex regimens

education

Hypoglycaemia
“Head in the sand”

Barriers
Excess weight gain
“I can do it with lifestyle”

Patient perceptions of Health service delivery

worsening disease

Patient perceptions of
insulin treatment and
Resource issues Financial restrictions
outcomes

Peyrot et al. Diabetes Care 2005;28:2673–9; Elgrably et al. Diabet Med 1991;8:773–7; Wallace & Matthews. QJM 2000;93:369–74;
Kunt & Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10
 Guideline
Recommendation
ADA position statement
 Start with monotherapy unless:

A1c is greater than or equal to 9%, consider dual therapy

A1c is greater than or equal to 10 %, blood glucose is greater than or equal to 300 mg/dL
or patient is markedly symptomatic, consider combination injectable therapy

Monotherapy Metformin Lifestyle Management

EFFICACY* high

HYPO RISK low risk

WEIGHT neutral/loss

SIDE EFFECTS GI/lactic acidosis

COSTS* low

If A1c is not achieved approximately after 3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference- choice
dependent on variety of patient- & disease-specific factors)

Dual Therapy Metformin + Lifestyle Management

Sulfonylurea Thiazolidinedione DPP-4 inhibitor SGLT2 inhibitor GLP-1 receptor agonist Insulin (Basal)

EFFICACY* high high intermediate intermediate high highest

HYPO RISK moderate risk low risk low risk low risk low risk high risk

WEIGHT gain gain neutral loss loss gain

SIDE EFFECTS hypoglycemia Edema, HF, fxs rare GU, dehydration, fxs GI hypoglycemia

COSTS* low low high high high high

If A1c is not achieved approximately after 3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference-
choice dependent on variety of patient- & disease-specific factors)
Diabetes Care 2017;40(Suppl. 1):S1–S138
 Contd.
Dual Therapy

Triple Therapy Metformin + Lifestyle Management

Sulfonylurea + Thiazolidinedione + DPP-4 inhibitor + SGLT2 inhibitor + GLP-1 receptor agonist + Insulin (Basal) +

TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or SGLT2-i or

SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin $ or GLP-1-RA or Insulin $ or GLP-1-RA

or Insulin $ or Insulin $ or Insulin $

If A1c is not achieved approximately after 3 months of triple therapy, and patient (1) on oral combination, move to basal insulin or GLP-1 RA, (2) on GLP-1 RA, add
basal insulin or (3) on optimally titrated basal insulin, addaGLP-1 RA or meal time insulin. Metformin therapy should be maintained, while other oral agents may be
discontinued on an individual basis to avoid unnecessary complex or costly regimens. (i.e. adding fourth antihyperglycemic agent).

Combination Injectable Therapy

Fig.8.1: Antihyperglycemic therapy in type 2 diabetes: general recommendations. The order in the chart is determined by historical availability and the route of administration,
with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the
usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor;
fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD,
thiazolidinedione. $ Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al 2015

*Inzucchi SE, Bergenstal RM, Buse JB, et al.Management of hyperglycemia in type 2 diabetes,2015: a patient-centered approach: update to a position statement of the American Diabetes
Association and the European Association for the Studyof Diabetes. Diabetes Care 2015;38:140–149
Diabetes Care 2017;40(Suppl. 1):S1–S138
Fig. 8.2
Combination injectable therapy
for type 2 diabetes
Adapted with permission from Start: 10U/day or 0.1-0.2 U/Kg/day
Inzucchi et al. Adjust: 10-15% or 2-4 units once or twice weekly to reach FBG target
For Hypo: Determine & address cause; if no clear reason for hypo, dose by 4 units or
10-20%
Add 1 rapid-acting insulin injection
before largest meal
Start: 4 units, 0.1 U/Kg/day or 10% basal dose.
If A1c <8%,consider basal by same amount
Adjust: dose by 1-2 units or 10-15% once or
twice weekly until SMBG target reached
For Hypo: Determine & address cause; if no clear
reason for hypo, dose by 2-4 units or 10-20%
If A1c is not controlled,
advance to basal bolus
Add ≥ 2 rapid-acting insulin injection
before meals (‘basal-bolus’)
Start: 4 units, 0.1 U/Kg/day or 10% basal dose. If
A1c <8%, consider basal by same amount
Adjust: dose(s) by 1-2 units or 10-15% once or
twice weekly to achieve SMBG target.
For Hypo: Determine & address cause; if no clear
reason for hypo, dose by 2-4 units or 10-20%
Initiate basal Insulin
Usually with metformin +/- other noninsulin agent
If A1c not controlled, consider combination injectable
therapy
Add GLP-1 RA
If not tolerated or A1C target not
reached, change to 2 insulin injection
regimen
If goals are not met, consider
changing to alternative
insulin regimen
If goals are not met, consider
changing to alternative
insulin regimen
Diabetes Care 2017;40(Suppl. 1):S1–S138
Change to premixed insulin twice daily
(before breakfast and supper)
Start: Divide current basal dose into 2/3 AM, 1/3
PM or ½ AM, ½ PM
Adjust: dose by 1-2 units or 10-15% once or
twice weekly until SMBG target reached
For Hypo: Determine & address cause; if no clear
reason for hypo, dose by 2-4 units or 10 -20%
If A1c is not controlled,
advance to 3rd injection
Change to premixed analog insulin 3
times daily (breakfast, lunch, supper)
Start: Add additional injection before lunch
Adjust: dose(s) by 1-2 units or 10-15% once
or twice weekly to achieve SMBG target.
For Hypo: Determine & address cause; if no
clear reason for hypo, dose by 2-4 units or 10-
20%
Ideal Basal Insulin
Characteristics
 25 March 2016 14

Physiological Pattern of Insulin Secretion

Mealtime insulin excursions.
Rapid rise; short duration
50
Serum insulin (mU/l)
40

30

20 Flat basal insulin profile

10

0
0800 1200 1600 2000 2400 0400 0800
Breakfast Lunch Dinner
Characteristics of an Ideal Basal Insulin

• Long action profile

• Minimal peak -Low variability
• As “physiological” as possible
• Produces less hypoglycaemia
• Enables better glycemic control
• Limits weight gain
• As convenient as possible to administer (soluble/device)
Insulin Detemir
a unique molecule
 Introduction: purpose of insulin detemir

The purpose of the development of insulin detemir was to create an

insulin that compared with conventional basal insulin has:
• a longer action profile
• less pronounced peak activity
• less intra-patient variability

Insulin detemir is indicated for the treatment of diabetes mellitus (T1D and T2D) in adults
(including pregnancy), adolescents and children aged ≥1 year in Europe (≥2 years in the
USA)1,2

T1D, type 1 diabetes; T2D, type 2 diabetes

1. Levemir. Summary of product characteristics, 2015; 2. Levemir. Prescribing information, 2015

 Insulin detemir molecule: monomer
Des threonine (B30) + myristic (mir) acid (B29)

C14 fatty acid chain

(Myristic acid) Tyr Phe Phe Gly
Thr Arg
Pro Glu
Lys
B29 Gly
Thr
Cys
A21 Asn Cys Val
Tyr
Asn Leu
Glu Tyr
A1 Gly Leu Leu
Ile Ala
Gln
Val Glu
Tyr
Glu Val
Leu
Gln Leu
Cys Cys Thr Ser Ile Cys Ser
Hls
Ser
Gly
B1 Phe Val Asn Gln Hls Leu
Cys A-chain
B-chain
Myristic acid residue

Novo Nordisk. Insulin detemir prescribing information, 2015

Insulin Detemir:
25 March 2016 19

Potential sites of protraction of action

Major protraction
Subcutaneous • Self-association (hexameric)
depot • Fatty-acid side chains bind to albumin
in injection depot

Minor protraction
• Albumin binding in circulation
Circulation • Buffering against variable absorption

No further protraction

Interstitial fluid Delivery to receptors

Hamilton-Wessler et al. Diabetologia 1999;42:1254–63

Advantages of unique and novel protraction
principle

• Predictability
• To get a blood glucose control which is less variable from day to day with
the same insulin dose

• Duration of action
• To provide 24-hours insulin action consistently across all patient groups
Less Intra – Patient variability:
Glucose variability predicts future risk of hypoglycaemia

12. 21
0 6
11. Average 19
0 FPG 8
10. 18
0 0
9.0 16
2
8.0
FPG (mmol/L)

14

FPG (mg/dL)
4
7.0 12
6
6.0 10
8
5.0 90
Target zone
4.0 72
3.0 54
2.0 Hypoglycaemia zone 36
1.0 18
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Day

FPG, fasting plasma glucose

Adapted from Kovatchev et al. Diabetes Care 2006;29:2433–8
Lower variability may reduce the risk of hypoglycaemia

12. 21
0 6
11. Average 19
0 FPG 8
10. 18
0 0
9.0 16
2
8.0
FPG (mmol/L)

14

FPG (mg/dL)
4
7.0 12
6
6.0 10
8
5.0 90
Target zone
4.0 72
3.0 54
2.0 Hypoglycaemia zone 36
1.0 18
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Day

FPG, fasting plasma glucose

Adapted from Kovatchev et al. Diabetes Care 2006;29:2433–8
Peak profiles and intra-patient variability
6 6 6
(mg/kg/min)

NPH 0.4 U/kg

4 4 4 IGlar U100 0.4 U/kg
GIR

2 2 2 100 IDet 0.4 U/kg

Intra-patient variability
0 0 0
0 8 16 24 0 8 16 24 0 8 16 24 80
6 6 6
(mg/kg/min)

4 4 4 60 68
GIR

(CV%)
2 2 2
40 48
0 0 0
0 8 16 24 0 8 16 24 0 8 16 24
6 6 6 20 27
(mg/kg/min)

4 4 4
0
GIR

2 2 2
NPH IGlar IDet
0
0 8 16 24
0
0 8 16 24
0
0 8 16 24 U100
Time (hours) Time (hours) Time (hours)

CV, coefficient of variation; GIR, glucose infusion rate; IDet, insulin detemir; IGlar U100, insulin glargine U100; NPH, neutral protamine Hagedorn
Heise et al. Diabetes 2004;53:1614–20
 From Theory to
Clinical Practice!
Comparable HbA1c reductions between insulin detemir,
NPH insulin and insulin glargine: type 1 diabetes

Insulin detemir NPH Insulin glargine

9.0
baseline to endpoint (%)

8.5
Change in HbA1c,

8.0

*
7.5
†‡
* *
7.0
##
#
6.5

*p<0.05

†IDet (AM + pre-dinner); ‡IDet (AM + bed); #IDet (12 hourly); ##IDet (AM + bed); ¶Treat-to-target
IDet, insulin detemir; NPH, neutral protamine Hagedorn
Successful reduction in FPG with insulin detemir in basal–
oral therapy treat-to-target trials: type 2 diabetes

Insulin detemir Insulin glargine NPH insulin

mg/dL (mmol/L) mg/dL (mmol/L) mg/dL (mmol/L)

Philis-Tsimikas 2006 -67.2 (-3.7) – -66.7 (-3.7)

Hermansen 2006 -75.7 (-4.2) – -75.7 (-4.2)

Riddle 2003 – -81.0 (-4.5) - 74.0 (-4.1)

OD: -54.0 (-3.0)

Rosenstock 2008 -68.5 (-3.8) –
BD: -79.0 (-4.4)

Meneghini 2013 -44.8 (-2.5) -43.4 (-2.4) –

p=non-significant for all

NPH, neutral protamine Hagedorn; FPG, fasting plasma glucose; OD, once daily; BD, twice daily
Hypoglycemic Reduction with Detemir Than
Glargine
18 Insulin Detemir
21% risk reduction
p <0.02

Events per patient per year

16 Insulin Glargine

14
47% risk reduction
12 p < 0.001z

10
8
42% risk reduction
6 p <0.01
4
2 55% risk reduction
p < 0.001
0
Overall Nocturnal
Hypoglycaemia

Riddle et al. Diabetes Care 2003, 26:3080-3086

Hermansen et al. Diabetes Care 2006, 29: 1269-1274
 Weight sparing: mechanism

Food
intake The weight-sparing properties
hypothes of insulin detemir are probably
is mediated directly or indirectly
through CNS-mediated reduced
Less- energy intake and partial
Fluid restoration of the normal
retention weight-gain CNS
effect of hypothe hepatic/peripheral insulin
hypothes
is insulin sis gradient
detemir
The weight-sparing properties of
Hepatoselec insulin detemir are unlikely to
tive involve reduced risk of
hypothesis hypoglycaemia or reduced fluid
retention
CNS, central nervous system

Russell-Jones et al. Diabetes Obes Metab 2015;doi:10.1111/dom.12493

 Special populations: Approved in pregnancy &
children (starting from 1 year)
• Efficacy and safety in children with
type 1 diabetes
• Insulin Detemir vs. NPH

• Insulin Detemir is approved in

children (aged 1 year and above)

• Insulin Detemir is approved in

GDM as category “B”.

NPH, neutral protamine Hagedorn

Dosage Guidelines
 Titration algorithm for Detemir

Change in evening dose of insulin Change in morning dose

Average predinner
detemir based of insulin detemir based
or prebreakfast PG
on prebreakfast PG on predinner PG
6 mmol/L (108 mg/dL, target) No adjustment No adjustment
6.0–7.0 mmol/L (109–126 mg/dL) +2 units +2 units
7.0–8.0 mmol/L (127–144 mg/dL) +4 units +2 units
8.0–9.0 mmol/L (145–162 mg/dL) +6 units +4 units
9.0–10.0 mmol/L (163–180 mg/dL) +8 units +6 units
>10 mmol/L (180 mg/dL) +12 units +8 units

If one or more prebreakfast or predinner PG values for both algorithms were:

<3.1 mmol/L (56 mg/dL) −4 units −4 units
3.1–4.0 mmol/L (56–72 mg/dL) −2 units −2 units

PG, plasma glucose

Raskin et al. Diabetes Metab Res Rev 2009;25:542–8

 33

Levemir Flexpen
Summary
Once-daily Levemir® -

● achieves a great reduction of HbA1c in type 2 DM

● is associated with less weight gain than NPH or glargine

● reduces the risks of overall and nocturnal hypoglycaemia

compared to NPH

● Safe to use in pregnancy and children (starting from 1 year)

Thank You