Clinical Use of Insulin Therapy

John B. Buse, MD, PhD

Professor of Medicine
Chief, Division of Endocrinology
Executive Associate Dean for Clinical Research
University of North Carolina School of Medicine
Chapel Hill, North Carolina, USA
Normal Secretory Pattern of Insulin

“Prandial” Insulin

Insulin
Level

“Basal” Insulin

SLEEP
Breakfast Lunch Dinner
Pharmacokinetic Profiles of Insulin Products

Rapid (Lispro, Aspart, Glulisine)

Insulin Short (Regular)

Level
Intermediate (NPH, Lente)
Long (Glargine)

Long (Detemir)

0 2 4 6 8 10 12 14 16 18 20 22 24

Hours
Common Insulin Regimens:
Type 2 Diabetes

• Basal Insulin (plus oral agents)

– Single dose glargine, detemir, NPH

• Conventional “Mixed” Insulin Therapy

– NPH plus short-/rapid-acting insulin

• Multiple Daily Injections (MDI)

– Long-acting insulin + mealtime insulin
The ADA Treatment Algorithm
for the Initiation
and Adjustment of Insulin
 Initiating and Adjusting Insulin
Hypoglycemia
or fg <3.89 mmol/l (70 mg/dl):
Reduce bedtime dose by ≥4 units
(or 10% if dose >60 units)
Continue regimen; check
A1C every 3 months
Pre-lunch bg out of range: add
rapid-acting insulin at breakfast
Continue regimen; check
HbA1C every 3 months
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Bedtime intermediate-acting insulin, or
bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg) Target Range:
Check fg and increase dose until in target range.
3.89-7.22 mmol/l
(70-130 mg/dl)
If A1C <7%... If A1C 7%...
If fasting bg in target range, check bg before lunch, dinner and bed.
Depending on bg results, add second injection
(can usually begin with ~4 units and adjust be 2 units every 3 days until bg in range)
Pre-dinner bg out of range: add NPH insulin at Pre-bed bg out of range: add
breakfast or rapid-acting at lunch rapid-acting insulin at dinner
If A1C <7%... If A1C 7%...
Recheck pre-meal bg levels and if out of range, may need to add another
injection; if A1C continues to be out of range, check 2-h postprandial levels and
adjust preprandial rapid-acting insulin
 Step One…
Bedtime intermediate-acting insulin, or
Hypoglycemia bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg) Target Range:
or fg <3.89 mmol/l (70 mg/dl):
Reduce bedtime dose by ≥4 units Check fg and increase dose until in target range.
3.89-7.22 mmol/l
(or 10% if dose >60 units) (70-130 mg/dl)

If A1C <7%... If A1C 7%...

Continue regimen; check If fasting bg in target range, check bg before lunch, dinner and bed.
HbA1C every 3 months Depending on bg results, add second injection
(can usually begin with ~4 units and adjust be 2 units every 3 days until bg in range)

Pre-lunch bg out of range: add Pre-dinner bg out of range: add NPH insulin at Pre-bed bg out of range: add
rapid-acting insulin at breakfast breakfast or rapid-acting at lunch rapid-acting insulin at dinner

If A1C <7%... If A1C 7%...

Continue regimen; check Recheck pre-meal bg levels and if out of range, may need to add another
A1C every 3 months injection; if A1C continues to be out of range, check 2-h postprandial levels and
adjust preprandial rapid-acting insulin

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Step One: Initiating Insulin
• Start with either…
– Bedtime intermediate-acting insulin or
– Bedtime or morning long-acting insulin

Insulin regimes should be designed taking

lifestyle and meal schedule into account

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Treatment to Target Study Mean
A1C Concentrations During Study

Glargine
Mean A1C (%)

NPH

Target A1C (%)

Weeks

Riddle M et al. Diabetes Care 2003;26(11)3080.

Treatment to Target Study:
Symptomatic Hypoglycemia by Time

Basal Glargine
35 insulin *
* NPH
Hypoglycemia Episode

30
Patients (%) With 1

* * *

25
*
20
15
10
5
B L D
0
20 22 24 2 4 6 8 10 12 14 16 18 20
Time Of Day (Hours)

*p<0.05 vs insulin glargine

Hypoglycemia defined as PG 72 mg/dl (4 mmol/l)

Adapted from Riddle M et al. Diabetes Care 2003;26(11):3080.

Step One: Initiating Insulin, cont’d
• Check fasting glucose and increase dose until in
target range
– Target range: 70-130 mg/dl (3.89-7.22 mmol/l)
– Typical dose increase is 2 units every 3 days but if fasting
glucose >180 mg/dl (>10 mmol/l) can increase by large
increments (e.g., 4 units every 3 days)

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Step One: Initiating Insulin, cont’d
• If hypoglycemia occurs or if fasting glucose >70 mg/dl
(3.89 mmol/l)…
– Reduce bedtime dose by ≥4 units or 10% if dose >60 units

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

After 2-3 Months…
• If A1C is <7%...
– Continue regimen and check A1C every 3 months

• If A1C is ≥7%...
– Move to Step Two…

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

 Step Two…
Bedtime intermediate-acting insulin, or
Hypoglycemia bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg) Target Range:
or fg <3.89 mmol/l (70 mg/dl):
Reduce bedtime dose by ≥4 units Check fg and increase dose until in target range.
3.89-7.22 mmol/l
(or 10% if dose >60 units) (70-130 mg/dl)

If A1C <7%... If A1C 7%...

Continue regimen; check If fasting bg in target range, check bg before lunch, dinner and bed.
A1C every 3 months Depending on bg results, add second injection
(can usually begin with ~4 units and adjust be 2 units every 3 days until bg in range)

Pre-lunch bg out of range: add Pre-dinner bg out of range: add NPH insulin at Pre-bed bg out of range: add
rapid-acting insulin at breakfast breakfast or rapid-acting at lunch rapid-acting insulin at dinner

If A1C <7%... If A1C 7%...

Continue regimen; check Recheck pre-meal bg levels and if out of range, may need to add another
A1C every 3 months injection; if A1C continues to be out of range, check 2-h postprandial levels and
adjust preprandial rapid-acting insulin

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Step Two: Intensifying Insulin
If fasting blood glucose levels are in target range but A1C ≥7%,
check blood glucose before lunch, dinner and bed and add a
second injection:
• If pre-lunch blood glucose is out of range, add rapid-acting
insulin at breakfast
• If pre-dinner blood glucose is out of range add NPH insulin at
breakfast or rapid-acting insulin at lunch
• If pre-bed blood glucose is out of range, add rapid-acting
insulin at dinner

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Making Adjustments
• Can usually begin with ~4 units and adjust by 2 units every 3
days until blood glucose is in range

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

After 2-3 Months…
• If A1C is <7%...
– Continue regimen and check HbA1c every 3 months

• If A1C is ≥7%...
– Move to Step Three…

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

 Step Three…
Bedtime intermediate-acting insulin, or
Hypoglycemia bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg) Target Range:
or fg <3.89 mmol/l (70 mg/dl):
Reduce bedtime dose by ≥4 units Check fg and increase dose until in target range.
3.89-7.22 mmol/l
(or 10% if dose >60 units) (70-130 mg/dl)

If A1C <7%... If A1C 7%...

Continue regimen; check If fasting bg in target range, check bg before lunch, dinner and bed.
A1C every 3 months Depending on bg results, add second injection
(can usually begin with ~4 units and adjust be 2 units every 3 days until bg in range)

Pre-lunch bg out of range: add Pre-dinner bg out of range: add NPH insulin at Pre-bed bg out of range: add
rapid-acting insulin at breakfast breakfast or rapid-acting at lunch rapid-acting insulin at dinner

If A1C <7%... If A1C 7%...

Continue regimen; check Recheck pre-meal bg levels and if out of range, may need to add another
A1C every 3 months injection; if A1Ccontinues to be out of range, check 2-h postprandial levels and
adjust preprandial rapid-acting insulin

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Step Three:
Further Intensifying Insulin
• Recheck pre-meal blood glucose and if out of range, may need
to add a third injection

• If A1C is still ≥7%

– Check 2-h postprandial levels
– Adjust preprandial rapid-acting insulin

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Premixed Insulin
• Not recommended during dose adjustment

• Can be used before breakfast and/or dinner if the proportion

of rapid- and intermediate-acting insulins is similar to the fixed
proportions available

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

New Data Since the Consensus Panel Last
Updated the Recommendations
 Subjects failing to initiate prescribed insulin commonly reported
misconceptions regarding insulin risk (35% believed that insulin
causes blindness, renal failure, amputations, heart attacks, strokes,
or early death), plans to instead work harder on behavioral goals,
sense of personal failure, low self-efficacy, injection phobia,
hypoglycemia concerns, negative impact on social life and job,
inadequate health literacy, health care provider inadequately
explaining risks/benefits, and limited insulin self-management
training. . . Primary adherence for insulin may be improved
through better provider communication regarding risks, shared
decision making, and insulin self-management training.
Karter AJ et al. Diabetes Care 2010;33:733-35.
Three Way Randomisation
Glycemic target: A1C ≤6.5%

Add once (or twice) Add prandial insulin

daily basal insulin* if glycaemic target not met†

700 T2DM Add twice daily Add midday prandial insulin

on OAD R biphasic insulin* if glycaemic target not met†

Add thrice daily Add basal insulin

prandial insulin* if glycaemic target not met†

Randomisation One Two Three

visit year years years

* progress to more intensive insulin regimen only if clinically necessary

† stop sulphonylurea if taken
Insulin Injections & Glucose Measurements
Glucose targets
Fasting and pre-meal: 72-99 mg/dl (4.0-5.5 mmol/l)
Two-hour post meal: 90-126 mg/dl (5.0-7.0 mmol/l)

Biphasic
* *
Prandial
* * * * * * *
Basal < >
* *
Injection * Self-measured glucose
N Engl J Med 2007;357:1716-30.
Mean One-year Changes
p= 0.04
20 25
20
Mean percentage change

10 p<0.001 p<0.001 p<0.001 p<0.001 15

10
0 5
0
-10 Hypoglycemia
grade 2 or 3
-20 (events/pts/yr)

-30

Biphasic
-40 Prandial
HbA1C FPG PPG Weight
Basal
8.5 9.6 mmol/l 12.6 85.8 kg
(%) (173 mg/dl) mmol/l (188 lbs)
(227 mg/dl)

N Engl J Med 2007;357:1716-30.

 Relative Changes over 3 Years
and Hypoglycemia
Mean± 1SD

20 8
Biphasic insulin ± prandial
Prandial insulin ± basal
Mean relative change (%)

10

No. of Events/Patient/Yr
Basal insulin ± prandial
6
0

-10 4

-20
2
-30

-40 0
Glycated Fasting Postprandial Body Hypoglycaemia
Haemoglobin Plasma Glucose Weight Grade 2 or 3
Glucose
Baseline 8.5% 9.6 mmol/l 12.6 mmol/l 85.8 kg
value 173 mg/dl 227 mg/dl 188 lbs
p value 0.28 0.83 <0.001 0.20 <0.001
Summary
• Three-quarters of patients added a second insulin
• Those commencing therapy with a basal or prandial
insulin more often achieved glycemic targets than
patients commencing with a biphasic insulin
• Patients commencing therapy with basal insulin had
fewer hypoglycemic episodes and less weight gain

These findings provide clear evidence in people with type 2

diabetes to support starting insulin therapy with a once a
day basal insulin, and then adding a mealtime insulin if
glycemic targets are not met.

N Engl J Med 2009;361:1736-47.

 GINGER: Glargine/glulisine MDI vs 70/30
(analog or human)

HbA1C (%) Blood glucose (mmol/l)

9.0 13.3
8.8 Insulin glargine + insuline glulisine Insulin glargine + insuline glulisine
8.6 Premixed insulin Premixed insulin
8.4 11.0
8.2 Baseline
8.0
7.8 8.9
7.6
7.4 † ‡
7.2 6.7 § †
Endpoint
7.0
6.8
0.0 0.0 Bedtime

Bedtime
0 10 20 30 40 50 Fasting Lunch Dinner
Time (weeks) 03:00 hr 2 hr 2 hr 2 hr
post- post- post-
breakfast lunch dinner

Fritsche A et al. Diabetes Obes Metab 2010;12:115-23.

1.2.3 Study: Glargine Plus 1, 2 or 3
Doses of Glulisine

Subjects:
• Insulin naïve (785 entered study, 343 randomized) with type 2 diabetes
(A1C ≥8.0%)
• Receiving 2 or 3 OHAs for ≥3 months (OHAs continued except
sulfonylurea)
Additional insulin glulisine once daily (n=115)

Insulin glargine
(n=785) Additional insulin glulisine twice daily (n=113)

14 weeks
Randomization (subjects Additional insulin glulisine three times daily (n=115)
with A1C >7.0%, n=434)

24 weeks
Adapted from Raccah D.
http://www.fesemi.org/grupos/obesidad/noticias/ponencias_iv_reunion/Prof.%20Denis%20Raccah.pdf.
Accessed April 9, 2010. Cited as sanofi aventis, data on file.
1.2.3 Study: Glargine Plus 1, 2 or 3
Doses of Glulisine

Responders in the whole Evolution of A1C in the randomized

population (n=785) population (n=343)

Glargine Glargine plus glulisine

(alone) (patients with A1C >7%)
80
10.19
All subjects 10.0 10.19
% achieving HbA1C <7.0

(n=785) Additional 10.16

Glulisine 1x
subjects who
60 achieved Glulisine 2x
23% A1C <7.0% Glulisine 3x

HbA1c (%)
with glulisine
9.0
40 added to
glargine
37%
Subjects who 8.0
20 achieved A1C
<7.0% with 7.44
7.40
glargine during 7.29
run-in 7.0
0
Run in Randomization Wk 8 Wk 16 Wk 24
A1C in all subjects (n=785) = 9.8 at run-in and 7.3 at randomization
Adapted from Raccah D. http://www.fesemi.org/grupos/obesidad/noticias/ponencias_iv_reunion/Prof.%20Denis%20Raccah.pdf.
Accessed April 9, 2010. Cited as sanofi aventis, data on file.
 1.2.3 Study: Glargine Plus 1, 2 or 3
Doses of Glulisine

p=NS for all other pairwise comparisons

5 20 0.35

Confirmed symptomatic hypo

p=0.043
Mean body weight change

Severe or serious hypo

0.30

(event/patient-year)
(event/patient-year)
4
from baseline (kg)

15 17.1 0.30
3.9 0.25
3.7 3.8 0.26
3 12.9 0.20
10 12.2
2 0.15

5 0.10
1 0.10
0.05
0 0 0.00
x1 x2 x3 x1 x2 x3 x1 x2 x3
Glulisine Glulisine Glulisine

Adapted from Raccah D. http://www.fesemi.org/grupos/obesidad/noticias/ponencias_iv_reunion/Prof.%20Denis%20Raccah.pdf.

Accessed April 9, 2010. Cited as sanofi aventis, data on file.
OPAL: Glargine Plus Glulisine
at Breakfast or Main Meal

7.4
7.3 7.35
7.32 7.29
7.2
A1C (%)

7.1
7.0
7.03
6.99
6.9 6.94
6.8
6.7
0
Overall Breakfast Main meal
group group
Lankisch MR et al. Diabetes Obes Metab 2008;10:1178-85.
Lankisch MR et al. Diabetes Obes Metab 2008;10:1178-85.
Summary
• Insulin is the oldest, most studied and most effective
antihyperglycemic agent but can cause weight gain (2-4 kg)
and hypoglycemia

• Insulin analogues with longer, non-peaking profiles may

decrease the risk of hypoglycemia compared with NPH insulin

• Premix analog insulin is not recommended during

dose adjustment

• Generally stop secretagogues after insulin initiated

Summary, cont’d
• When initiating insulin, start with bedtime intermediate-acting
insulin, or bedtime, evening or morning long-acting insulin

• After 2-3 months, if FBG levels are in target range but A1C ≥7%,
check BG before lunch, dinner and bed, and, depending
on the results, add 2nd injection, generally of rapid-acting insulin.

• After 2-3 months, could consider adding a third injection,

though it would be important to assess the effectiveness of
such an approach.