Using Insulin in the Primary
Care Setting: Interactive Cases
Irl B. Hirsch, MD
University of Washington School of
Medicine
Dualities
(Nov, 2011)
 Research Grants: sanofi-aventis, Novo
Nordisk, Halozyme, Mannkind
 Consulting: Cellnovo, Roche, Johnson &
Johnson, Abbott Diabetes Care
Teaching Point 1, Case 1
 After 1 year of attempted weight loss and
rising A1C levels since his diagnosis, Mr.
Henry, 51 years-old, agrees it is time to start
insulin. His BMI is 28 kg/m2, his weight is 80
kg, his A1C is 8.8%, and he is currently
receiving metformin, glipizide, and
sitagliptin.
 Decision point 1- WHICH INSULIN/INSULIN
REGIMEN DO YOU START?
Treat-to-Target Trial
Change of A1c with systematic titration of basal insulin
Glargine
9
NPH
8.6 8.6
Mean A1c
%
8
7.5 7.4
7.1 7.1
6.9 6.9
6.9 6.9
7
58% ≤ 7%
6
0
4
8
12
16
Weeks of treatment
Riddle MC et al. Diabetes Care 2003;26: 3080-86
20
24
Consistent results using the Treat-to-Target
method with glargine as basal insulin
Baseline
Study end
9.5
9.0
HbA1C (%)
8.5
8.0
7.5
7.0
6.5
8.6
8.6
8.7
8.8
8.7
Teaching
people∆ -1.7
∆ -1.6Point∆ 1:
-1.7 Most∆ -2.0
can reach an A1C < 7% with
7.0
7.0
7.0
7.0
6.8
basal insulin alone with baseline
A1C levels in the mid-8s
∆ -1.6
6.0
5.5
1.
2.
3.
4.
5
T-T-T1
n = 367
INSIGHT2
n = 206
Riddle M et al. Diabetes Care 2003;26:3080
Gerstein HC et al. Diabetes Med 2006;23:736
Bretzel RG et al. Lancet 2008;371:1073
Yki-Järvinen H et al. Diabetes Care 2007;30:1364
Schreiber SA et al. Diabetes Obes Metab 2007;9:31
APOLLO3
n = 174
INITIATE4
n = 58
Schreiber5
n = 12,216
Baseline A1c affects results of basal insulin Rx
2193 patients with 24 weeks systematically titrated glargine added to OAD
A1c change from baseline
% of patients attaining <7% A1c
TEACHING POINT 2: Final
A1C (with basal insulin) is
dependent on baseline A1C!
75
63
-0.9
-1.4
56
47
-1.6
34
-2.0
-2.6
<8.0
8.5-8.9
≥9.5
9.0-9.4
8.0-8.4
<8.0
8.0-8.4
8.5-8.9
9.0-9.4
≥9.5
75% of participants with baseline A1c <8% attained 7%
Riddle MC et al. Diabetes 2009;58(Suppl 1): A125
Baseline A1c does not affect hypoglycemia risk
2193 patients with 24 weeks systematically titrated glargine added to OAD
Hypoglycemia
confirmed <3.9 mmol/L (70 mg/dL)
Hypoglycemia
requiring assistance
50%
1.5%
<8.0
8.0-8.4
8.5-8.9
9.0-9.4
≥9.5
<8.0
8.0-8.4
8.5-8.9
9.0-9.4
≥9.5
Titration of insulin was stopped at appropriate levels of risk
Riddle MC et al. Diabetes 2009;58(Suppl 1): A125
Back to Mr. Henry
 15 units of insulin glargine is started, and over the
next 4 months his dose was titrated to 80 units daily
 The metformin, glipizide, and sitagliptin remained
unchanged; on glargine he has gained 3 kg
 After being on the 80 unit dose for 8 weeks, 5
months after starting the insulin, his A1C is 7.3%.
Fasting glucose levels are generally in the 130-140
mg/dL range.
 What now? A) Bump glargine to 90 u; B) Split
glargine to 40 u BID; C) SMBG to determine prandial
insulin needs; D) add pioglitazone; E) wait another 4
weeks to recheck the A1C
What About Dose Response to Insulin
Glargine in Obese Patients?
 20 subjects with type 2 diabetes (A1C 8.3%,
BMI 36 kg/m2) injected single injections of
insulin glargine into abdomen at 0, 0.5, 1.0,
1.5, and 2.0 units/kg body weight
 26-hour euglycemic clamp studies, so
conclusions longer than this time period were
not possible
Wang Z. Diabetes Care. 2010;33:1555-1560.
Glucose Infusion Rates (GIRs) for Different
Glargine Doses Injected into Abdomen
1.0, 1.5, and 2.0 units/kg > GIR
TEACHING POINT
3: although it is
than 0.5 units/kg, but not than
each other!
possible duration
of
1.5 insulin action is
1.0 units/kg
units/kg
2.0 units/kg
0.5
units/kg
prolonged with increasing doses of
glargine, there is no difference in insulin
action the 24 h after injection once dose
is > 1.0 u/kg
placebo
WAIT A MINUTE!
 Mr. Henry now has a BMI of 29.5 kg/m2, uses
an insulin pen for his insulin glargine-and he
needs all of his ‘scripts renewed. What size
pen needles do you write for?
Nano
Mini
Short Original
 A) 4 mm 32 G
 B) 5 mm 31 G
 C) 8 mm 31 G
 D) 12.7 mm 29 G
Distribution of Skin Thickness Values (in mm)
by Body Site and BMI
1. Small differences within
each body site: obese higher
(P<0.001)
2
kg/m
In perspective: a 10
change in BMI accounts for
2. Thigh lowest ST values
a 0.2 mm change in ST
3. Greatest difference
2. Mulitvariate analysis
between sites and genders
(P<0.001) but not age (NS)
thigh/buttocks 0.6 mm
Gibney MA et al: Curr Med Res
Opin. 2010 Jun;26(6):1519-30
Estimates of Intramuscular (IM) Injection
Risk from ST/SCT Data*
Pen Needle Length (mm)
4 mm
5 mm
6 mm
8 mm
12.7 mm
*Assume a 90-degree insertion without pinch-up.
injection sites combined (n = 1,208)
IM (%)
0.5
2.0
5.5
15.5
45.0
All
Gibney MA et al: Curr Med Res Opin. 2010 Jun;26(6):1519-30
Study Conclusions: 4 mm and 5 mm
vs. 8 mm Insulin Needles
 N= 328
 Equivalent glycemic control REGARDLESS
of BMI
 No differences in hypoglycemia between
needle lengths
 Strong preference for shorter needles
 Ease of use, pain, overall preference
Hirsch LJ. Curr Med Res Opin. 2010;26:1531–1541
Back to Mr. Henry
 A1C=7.3%, injecting 80 units of insulin
glargine with 4 mm needle q HS; also
receiving maximum dose metformin,
glipizide, sitagliptin
 He is asked to increase testing to 2-3X/day
 Tries to limit carbohydrates to no more than
60 grams/meal (met with nutritionist)
SMBG RESULTS
B’FAST LUNCH DINNER HS
MON
128
TUES
118
196
WED
136
177
285
THURS 128
144
FRI
162
SAT
142
SUN
122
0300 h
248
205
205
307
188
265
NOW WHAT?
 What to do with the glargine?
 What to do with prandial insulin?
 What to do with metformin, glipizide, and
sitagliptin?
What’s Next?
 Glargine is reduced to 70 units q HS
 Insulin aspart is started at dinner, 10 units
(10-15 min prior to dinner)
 Correction dose for any pre-meal BG: ISF 30
above 150
 150-180 +1 unit
241-270 +4 units
 181-210 +2 units
271-300 + 5 units
 211-240 + 3 units 301-330 + 6 units
 Sitagliptin is stopped!
NOW WHAT TO SUGGEST?
B’FAST
LUNCH
MON 116
TUE
125
162
10+1
142
WED 107
THU
DINNER HS
158
10
196
10+2
185
10+2
221
70G
207
70G
238
70G
224
70G
0300
Why the Interest In Glycemic
Variability?
 Experimental data suggests an increase in
oxidative stress and activation of
inflammation
 May be involved with pathogenesis of
vascular complications
 For those on insulin high variability predicts
severe hypoglycemia
 A marker of insulin deficiency and poor
matching of prandial insulin to carbohydrate
load
Which Patient Has More Variable
Fasting Glucose Data?
Joe: HbA1c = 6.5%; on
liraglutide
Mean = 123 mg%
SD = 51
60
148
70
165
54
286
203
112
110
185
210
69
68
138
144
75
138
192
114
52
Mary: HbA1c = 6.5%; on
metformin
Mean = 123 mg%
SD = 77
Standard Deviation
 Our clinically available measurement of
glycemic variability
 Many other statistical analysis are
available but correlation will be with
CGM and outcomes, not SMBG
 Can determine both overall and time
specific SD
 Need sufficient data points
 Minimum 5 but prefer 10
Calculation To Determine SD Target
SD X 2 < MEAN (T1DM)
 Ideally SD X 3 < mean
Significance of a High SD
 Insulin deficiency (especially good with fasting blood
glucose)
 Poor matching of calories (especially carbohydrates)
with insulin
 Giving mealtime insulin late (or missing shots
completely)
 Erratic snacking
 Poor matching of basal insulin, need for CSII?
CGM?
Caveats of the SD
 Need sufficient SMBG data
 Low or high averages makes the 2XSD<mean
rule irrelevant
Other Tricks To Reduce GV





Enough testing
Don’t over-treat the lows!
Reduce carbs
Pramlintide/exenatide
Lag times
Timing of Rapid-Acting Analog Insulin Injection
Alters PPG in Type 1 Diabetes Mellitus
288
BG Level (mg/dL)
252
216
Injection-Meal Interval
(minutes)
–30 m
–15 m
0m
+15 m
180
144
108
72
Injection-Meal Interval
(minutes)
288
–20 m
0m
+20 m
252
216
180
144
108
72
36
0
-30
Insulin Glulisine
BG Level (mg/dL)
Insulin Lispro
8.6 kcal/kg breakfast
0
30 60 90 120 150 180 210 240 270 300
Minutes
36
0
-30
Standardized breakfast
0
30 60 90 120 150 180 210 240 270 300
Minutes
Rassam AG, et al. Diabetes Care. 1999;22:133-136.
Cobry E, et al. Diabetes Technol Ther. 2010;12:173-177.
Now…Back to Mr. Henry
 He is currently taking insulin glargine, 50 u q
HS with premeal insulin aspart, 2-5 u ac
breakfast, 10-15 units ac lunch and dinner
with an insulin sensitivity factor of 25 (1 unit
corrects 25 mg/dL) above 150 before meals,
200 at HS.
 A1C = 6.7%
 What does the meter download suggest?
Mr. Henry’s Download Statistics
Summary (30 days)
Frequency of testing =
Fasting mean/SD:
AC lunch mean/SD:
AC dinner mean/SD
HS mean/SD:
Overall:
3.2X/day
114 + 24
122 + 42
140 + 49
179 + 88
135 + 42
Conclusions:
1. Still too much basal insulin
2. Needs help with dosing at dinner (missing doses?)
3. Still making lots of insulin!
4. Need to look at downloaded “logbook” to understand specifics (insulin not yet
downloadable) and if ISF is correct
Teaching Point 4
Downloading of glucose data is
extremely helpful to see patterns not
otherwise noted for those checking
more than 2X/day. These downloads
will become more accessible over the
next few years with the use of tablets
and smartphones
Mr. Spar Tan
 A 56 year-old mildly mentally retarded Caucasian man
presents with a random blood glucose found to be 435
mg/dL. There is no family history of diabetes.
 He lives with his brother who mentions nocturia and 10
pound weight loss over the past month. The patient’s
only complaint is erectile dysfunction.
 Exam is significant for a BMI of 32 kg/m2, BP 155/95,
HR 88, mild acanthosis nigricans, normal fundi and
vibratory sensation on his great toes.
Mr. Spar Tan, cont
 Glucose 435 mg/dL, all other electrolytes WNL
except sodium of 133.
 HbA1C 14.0% (normal 4-6%)
 Urine ketones: negative
What would you suggest at this time?
A) Begin combination glipizide/pioglitazone
B) Begin basal-bolus insulin
C) Begin basal insulin alone
D) Begin twice daily NPH/regular
Teaching Point(s) 5
 Type 1 diabetes can occur at any age
 Type 1 diabetes can occur in obese patients
 While acute presentation can be seen in type
2 diabetes, it is more common in type 1
diabetes and while sorting out the specific
etiology of the diabetes, initiating insulin is
never the wrong therapy
 The best two auto-antibodies for this age
group is GAD65 and IA-2 (ICA-512)
Mr. Bill Dog
Ms. Duck is a 54 year-old woman who will be having a
pancreatectomy . What will you tell her she will
require for insulin therapy after his surgery?
A.Basal insulin alone
B.Pre-mix insulin, 0.5 u/kg
C.Basal-bolus insulin, 0.7 u/kg
D.Basal-bolus insulin, 0.25 u/kg
E. GLP-1 receptor agonist
Teaching Point 6
 Pancreatectomized patients are glucagon
deficient, are very insulin sensitive, and are
prone to severe hypoglycemia
Mr. Grass Lee
 Mr. Lee, a convicted tax evader from Iowa, now
is an 81 year-old nursing home patient. He has a
known 10 year history of type 2 diabetes and
suffers from Alzheimer’s Disease and heart
failure from a previous MI
 In the nursing home over the past year he has
lost 12 pounds.
 For his diabetes he receives glyburide 10 mg BID
 His A1C is 10.4%. BID glucose testing shows all
levels between 220 and 280 mg/dL
 Other lab: creatinine 1.4, BUN 25, LDL-C 59
Mr. Lee (cont)






What to do now?
A) Nothing
B) Add a GLP-1 agonist
C) Add a thiazolidinedione
D) Add basal insulin
E) Begin basal-bolus insulin therapy
Teaching Point 7
 Many elderly patients become severely
insulin deficient and often insulin is required
to prevent severe symptoms, most notably
falling at night from using the bathroom
Mrs. PIA
 You receive a call at 5pm on a Friday from
Mrs Pia that she needs a new prescription
for insulin syringes. She takes 60 units of
insulin detemir at bedtime and insists she
uses a short insulin needle
 What kind of insulin syringe to you call for
her?
Teaching Point 8
 Insulin syringes come in 3 volumes: 1cc (100
units) ½ cc (50 units) and 0.3 cc (30 units)
Mr. Fred I. Zone
 A 55 year-old man with well-controlled type 2
diabetes treated with metformin is started on
prednisone, 40 mg/day for severe asthma.
 Random fingerstick glucose his second day after
starting the prednisone is 355 mg/dL
 What insulin regimen would serve Mr. Zone the
best?
 A) bedtime NPH
D) premeal lispro
 B) bedtime glargine
E) bedtime glargine,
premeal lispro
 C) BID 70/30 premix
Tough Case (if time!)
 A 53 year-old man with 5 years of type 2
diabetes presents with a HbA1c of 9.9%. He
and his wife are frustrated in that he limits
his carbohydrate and exercises 6X/week. His
BMI is 27 and his exam is unremarkable
other than he wears hearing aids. His insulin
dose is 60 units of insulin glargine twice
daily and premeal insulin lispro 40-50 units
before meals. He cramps with metformin and
pioglitazone had no impact on his glucose
levels. What would you do next?
Conclusions
 Our insulins are far from perfect, but if we
can be creative our patients can usually do
well
Thank You!