Using Insulin in the Primary Care Setting: Interactive Cases

1
Using Insulin in the Primary Care Setting
Interactive Cases

• Irl B. Hirsch, MD
• University of Washington School of Medicine

2
Dualities(Nov, 2011)

• Research Grants sanofi-aventis, Novo Nordisk,
  Halozyme, Mannkind
• Consulting Cellnovo, Roche, Johnson Johnson,
  Abbott Diabetes Care

3
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?

4
Treat-to-Target Trial Change of A1c with
systematic titration of basal insulin
9
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
20
24
Weeks of treatment
Riddle MC et al. Diabetes Care 200326 3080-86
5
Consistent results using the Treat-to-Target
method with glargine as basal insulin
Baseline
Study end
9.5
8.8
8.7
8.7
9.0
8.6
8.6
8.5
Teaching Point 1 Most people can reach an A1C lt
7 with basal insulin alone with baseline A1C
levels in the mid-8s
? -1.6
? -1.6
? -1.7
? -2.0
? -1.7
8.0
HbA1C ()
7.5
7.0
7.0
7.0
7.0
6.8
7.0
6.5
6.0
5.5
Schreiber5n 12,216
T-T-T1n 367
INSIGHT2 n 206
APOLLO3n 174
INITIATE4n 58

• Riddle M et al. Diabetes Care 2003263080
• Gerstein HC et al. Diabetes Med 200623736
• Bretzel RG et al. Lancet 20083711073
• Yki-Järvinen H et al. Diabetes Care 2007301364
• 5 Schreiber SA et al. Diabetes Obes Metab
  2007931

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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 lt7 A1c
TEACHING POINT 2 Final A1C (with basal insulin)
is dependent on baseline A1C!
Riddle MC et al. Diabetes 200958(Suppl 1) A125
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Baseline A1c does not affect hypoglycemia risk
2193 patients with 24 weeks systematically
titrated glargine added to OAD
Hypoglycemia requiring assistance
Hypoglycemia confirmed lt3.9 mmol/L (70 mg/dL)
50
1.5
Titration of insulin was stopped at appropriate
levels of risk
Riddle MC et al. Diabetes 200958(Suppl 1) A125
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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

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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. 2010331555-1560.
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Glucose Infusion Rates (GIRs) for Different
Glargine Doses Injected into Abdomen
TEACHING POINT 3 although it is possible
duration of insulin action is prolonged with
increasing doses of glargine, there is no
difference in insulin action the 24 h after
injection once dose is gt 1.0 u/kg
1.0, 1.5, and 2.0 units/kg gt GIR than 0.5
units/kg, but not than each other!
1.5 units/kg
1.0 units/kg
2.0 units/kg
0.5 units/kg
placebo
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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?
• A) 4 mm 32 G
• B) 5 mm 31 G
• C) 8 mm 31 G
• D) 12.7 mm 29 G

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Distribution of Skin Thickness Values (in mm)by
Body Site and BMI

• Small differences within each body site obese
  higher (Plt0.001)
• Mulitvariate analysis between sites and genders
  (Plt0.001) but not age (NS)
• 2. Thigh lowest ST values
• 3. Greatest difference thigh/buttocks 0.6 mm

In perspective a 10 kg/m2 change in BMI accounts
for a 0.2 mm change in ST
Gibney MA et al Curr Med Res Opin. 2010
Jun26(6)1519-30
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Estimates of Intramuscular (IM) Injection Risk
from ST/SCT Data
Pen Needle Length (mm) IM () 4 mm
0.5 5 mm 2.0
6 mm
5.5 8 mm 15.5 12.7 mm
45.0
Assume a 90-degree insertion without pinch-up.
All injection sites combined (n 1,208)
Gibney MA et al Curr Med Res Opin. 2010
Jun26(6)1519-30
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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. 20102615311541
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Back to Mr. Henry

• A1C7.3, 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)

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SMBG RESULTS
BFAST LUNCH DINNER HS 0300 h
MON 128 285
TUES 118 196
WED 136 177 248
THURS 128 144 205
FRI 162 205 307
SAT 142
SUN 122 188 265
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NOW WHAT?

• What to do with the glargine?
• What to do with prandial insulin?
• What to do with metformin, glipizide, and
  sitagliptin?

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Whats 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!

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NOW WHAT TO SUGGEST?
BFAST LUNCH DINNER HS 0300
MON 116 162 101 221 70G
TUE 125 142 10 207 70G
WED 107 196 102 238 70G
THU 158 185 102 224 70G
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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

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Which Patient Has More Variable Fasting Glucose
Data?
60 54
148 286
70 203
165 112
110 69
185 68
210 138
144 192
75 114
138 52
Joe HbA1c 6.5 on liraglutide
Mary HbA1c 6.5 on metformin
Mean 123 mg Mean 123 mg
SD 51 SD 77
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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

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Calculation To Determine SD Target
SD X 2 lt MEAN (T1DM)

• Ideally SD X 3 lt mean

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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?

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Caveats of the SD

• Need sufficient SMBG data
• Low or high averages makes the 2XSDltmean rule
  irrelevant

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Other Tricks To Reduce GV

• Enough testing
• Dont over-treat the lows!
• Reduce carbs
• Pramlintide/exenatide
• Lag times

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Timing of Rapid-Acting Analog Insulin Injection
Alters PPG in Type 1 Diabetes Mellitus
Injection-Meal Interval (minutes)
Insulin Lispro
Insulin Glulisine
Injection-Meal Interval (minutes)
288
288
30 m 15 m 0 m 15 m
20 m 0 m 20 m
252
252
216
216
180
180
BG Level (mg/dL)
BG Level (mg/dL)
144
144
108
108
72
72
36
36
8.6 kcal/kg breakfast
Standardized breakfast
0
0
300
-30
0
30
60
240
90
270
120
150
180
210
300
-30
0
30
60
240
90
270
120
150
180
210
Minutes
Minutes
Rassam AG, et al. Diabetes Care.
199922133-136. Cobry E, et al. Diabetes Technol
Ther. 201012173-177.
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NowBack 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?

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Mr. Henrys Download Statistics Summary (30 days)
Frequency of testing 3.2X/day Fasting
mean/SD 114 24 AC lunch mean/SD 122
42 AC dinner mean/SD 140 49 HS
mean/SD 179 88 Overall 135 42

• Conclusions
• Still too much basal insulin
• Needs help with dosing at dinner (missing doses?)
• Still making lots of insulin!
• Need to look at downloaded logbook to
  understand specifics (insulin not yet
  downloadable) and if ISF is correct

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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
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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
  patients 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.

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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
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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)

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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?

• Basal insulin alone
• Pre-mix insulin, 0.5 u/kg
• Basal-bolus insulin, 0.7 u/kg
• Basal-bolus insulin, 0.25 u/kg
• GLP-1 receptor agonist

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Teaching Point 6

• Pancreatectomized patients are glucagon
  deficient, are very insulin sensitive, and are
  prone to severe hypoglycemia

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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 Alzheimers 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

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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

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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

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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?

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Teaching Point 8

• Insulin syringes come in 3 volumes 1cc (100
  units) ½ cc (50 units) and 0.3 cc (30 units)

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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

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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?

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Conclusions

• Our insulins are far from perfect, but if we can
  be creative our patients can usually do well

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Thank You!