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?

6

7

8

9

0 4 8 12 16 20 24

Weeks of treatment

8.6 8.6

7.5 7.4

7.1 7.16.9 6.9 6.9 6.9

Glargine NPHMean A1c

%

58% ≤ 7%

Riddle MC et al. Diabetes Care 2003;26: 3080-86

Treat-to-Target Trial Change of A1c with systematic titration of basal insulin

Consistent results using the Treat-to-Target method with glargine as basal insulin

1. Riddle M et al. Diabetes Care 2003;26:30802. Gerstein HC et al. Diabetes Med 2006;23:736 3. Bretzel RG et al. Lancet 2008;371:10734. Yki-Järvinen H et al. Diabetes Care 2007;30:13645 Schreiber SA et al. Diabetes Obes Metab 2007;9:31

Baseline Study end

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

T-T-T1

n = 367INSIGHT2

n = 206APOLLO3

n = 174INITIATE4

n = 58Schreiber5

n = 12,216

Hb

A1C

(%

)

8.6 8.6 8.7 8.78.8

7.0 7.0 7.0 6.8 7.0

∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7Teaching Point 1: Most people can reach an A1C < 7% with

basal insulin alone with baseline A1C levels in the mid-8s

A1c change from baseline % of patients attaining <7% A1c

Baseline A1c affects results of basal insulin Rx

Riddle MC et al. Diabetes 2009;58(Suppl 1): A125

2193 patients with 24 weeks systematically titrated glargine added to OAD

75

-0.963

5647

34-1.4

-1.6

-2.0

-2.6

75% of participants with baseline A1c <8% attained 7%

TEACHING POINT 2: Final A1C (with basal insulin) is

dependent on baseline A1C!

Hypoglycemiaconfirmed <3.9 mmol/L (70 mg/dL)

Hypoglycemiarequiring assistance

Baseline A1c does not affect hypoglycemia risk2193 patients with 24 weeks systematically titrated glargine added to OAD

Riddle MC et al. Diabetes 2009;58(Suppl 1): A125

<8.08.0-8.4

8.5-8.99.0-9.4

≥9.5

Titration of insulin was stopped at appropriate levels of risk

50%

1.5%

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

1.5 units/kg 2.0 units/kg0.5 units/kg

placebo

1.0, 1.5, and 2.0 units/kg > GIR than 0.5 units/kg, but not than each other!

1.0 units/kg

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 > 1.0 u/kg

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

Nano Mini Short Original

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. Mulitvariate analysis between sites and genders (P<0.001) 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 Jun;26(6):1519-30

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 Jun;26(6):1519-30

Hirsch LJ. Curr Med Res Opin. 2010;26:1531–1541

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

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 RESULTSB’FAST 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

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 DINNER HS 0300

MON 116 162 10+1

221 70G

TUE 125 142 10

207 70G

WED 107 196 10+2

238 70G

THU 158 185 10+2

224 70G

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?

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

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

Ideally SD X 3 < mean

SD X 2 < MEAN (T1DM)SD X 2 < MEAN (T1DM)

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

300

Timing of Rapid-Acting Analog Insulin Injection Alters PPG in Type 1 Diabetes Mellitus

Rassam AG, et al. Diabetes Care. 1999;22:133-136.Cobry E, et al. Diabetes Technol Ther. 2010;12:173-177.

8.6 kcal/kg breakfast

Minutes

BG

Lev

el

(mg

/dL

)

288

252

216

180

144

108

72

36

0-30 0 30 60 24090 270120 150 180 210

–30 m–15 m

0 m+15 m

Injection-Meal Interval (minutes)

Insulin Lispro

300

Standardized breakfast

Minutes

BG

Lev

el

(mg

/dL

)

288

252

216

180

144

108

72

36

0-30 0 30 60 24090 270120 150 180 210

–20 m0 m

+20 m

Insulin Glulisine Injection-Meal Interval (minutes)

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 = 3.2X/dayFasting mean/SD: 114 + 24AC lunch mean/SD: 122 + 42AC dinner mean/SD 140 + 49HS mean/SD: 179 + 88Overall: 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/pioglitazoneB) Begin basal-bolus insulinC) Begin basal insulin aloneD) 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 aloneB.Pre-mix insulin, 0.5 u/kgC.Basal-bolus insulin, 0.7 u/kgD.Basal-bolus insulin, 0.25 u/kgE. 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!