American College of Physicians Internal Medicine 2011

Insulin for the Internist

MTP 013 A MTP 013 B

Faculty
Professor: Irl B. Hirsch, MD, FACP Disclosure: Research Grants/Contracts: Novo Nordisk; Consultantship: Roche, Bayer, Abbott, Animas; Clinical questions to be addressed: 1.How does one decide when and how (for example, which type of insulin regimen) to initiate insulin? 2.What self-management tools should most patients understand (mealtime dosing and correction-dose insulin)? 3.How does one decide when adjustments in insulin dosing are appropriate and what tools can be used to make these decisions? 4.Describe how to interpret downloaded glucose levels and translate them into insulin adjustments.

Posted Date: March 8, 2011

2011 American College of Physicians. All rights reserved. Reproduction of Internal Medicine 2011 presentations, or print or electronic material associated with presentations, is prohibited without written permission from the ACP.

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INSULIN FOR THE INTERNIST

Irl B. Hirsch, MD FACULTY DISCLOSURE DECLARATION

FINANCIAL OR OTHER RELATIONSHIP(S) DISCLOSURE: Dr. Hirsch has indicated that he has had financial or D Hi h h i di t d th t h h h d fi i l other relationships with commercial interests within the past 12 months as follows: Consulting/Speaking/Teaching: Roche, J&J, Bayer, Abbott, Boehinger Ingelheim Grant/Research Support: Novo Nordisk, Mannkind Corp, Halozyme

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

Impact of Intensive Therapy in Diabetes Summary of Major Clinical Trials

Study DCCT/EDIC UKPDS ACCORD ADVANCE VADT Microvascular CVD Mortality

Individualized Targets

The available evidence, albeit limited, suggests that in younger patients with relatively recent onset of T2DM and little, if any, micro- and macrovascular complications, near-normal glycemic targets should be the standard. Here, the aim is to help prevent complications over the many years of life. In older individuals with longstanding T2DM and evidence of CVD (or multiple CVD risk factors), somewhat higher targets should be considered.
Ann Intern Med, 2011, in press

Initial Trial Long Term Follow-up Follow-

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
9

Glargine
8.6 8.6

NPH

Mean A1c %
8

7.5 7.4 7.1 7.1 6.9 6.9 6.9 6.9

58% 7%
6 0 4 8 12 16 20 24

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

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Consistent results using the Treat-to-Target method with glargine as basal insulin
Baseline
9.5 9.0 8.5 HbA1C (% %) 8.0 7.5 7.0 6.5 6.0 5.5 8.6 -1.6 8.6 8.7 8.8 8.7

Baseline A1c affects results of basal insulin Rx

2193 patients with 24 weeks systematically titrated glargine added to OAD

Study end

A1c change from baseline

% of patients attaining <7% A1c

Teaching Point 1: Most -2.0 -1.6 -1.7 people -1.7 can reach an A1C < 7% with h ith 7.0 7.0 7.0 7.0 6.8 basal insulin alone with baseline A1C levels in the mid-8s
T-T-T1 n = 367 INSIGHT2 n = 206 APOLLO3 n = 174 INITIATE4 n = 58 Schreiber5 n = 12,216

TEACHING POINT 2: Final A1C (with basal insulin) is dependent on baseline A1C!
75 -0.9 63 56 -1.4 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

1. 2. 3. 4. 5

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-Jrvinen H et al. Diabetes Care 2007;30:1364 Schreiber SA et al. Diabetes Obes Metab 2007;9:31

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

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 (7.2-7.8 mM) 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

Hypoglycemia confirmed <3.9 mmol/L

50%

Hypoglycemia requiring assistance

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

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

Glucose Infusion Rates (GIRs) for Different Glargine Doses Injected into Abdomen
1.0, 1.5, and GIR TEACHING POINT 2.0 units/kg >than 3: although it is than 0.5 units/kg, but not each other! possible duration of insulin action is 1.5 1.0 units/kg units/kg 0.5 units/kg prolonged with increasing2.0 units/kg of doses glargine, there is no difference is insulin action the 24 h after injection once dose is > 1.0 u/kg placebo

Wang Z. Diabetes Care. 2010;33:1555-1560.

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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? 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. 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
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)

Study Conclusions: 4 mm and 5 mm vs. 8 mm Insulin Needles

N= 328 Equivalent glycemic control REGARDLESS of BMI N diff No differences in hypoglycemia between i h l i b t needle lengths Strong preference for shorter needles Ease of use, pain, overall preference
Hirsch LJ. Curr Med Res Opin. 2010;26:15311541

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

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, 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)
MON TUES WED FRI SAT SUN 142 122 128 118 136

SMBG RESULTS
BFAST LUNCH DINNER HS 285 196 177 144 162 205 188 307 265 248 205 0300 h

THURS 128

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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? it li ti ?

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 p y 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?

BFAST MON 116 TUE 125 142 10 196 10+2 185 10+2 LUNCH DINNER HS 162 10+1 221 70G 207 70G 238 70G 224 70G 0300

How Has Our Ability To Capture Home Glucose Data Changed Over The Past 90 Years?

WED 107 THU 158

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 60 148 70 165 110 185 210 144 75 138 54 286 203 112 69 68 138 192 114 52 Mary: HbA1c = 6.5%; on metformin

Mean = 123 mg/dL

Mean = 123 mg/dL

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

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

Ideally SD X 3 < mean

Minimum 5 but prefer 10

Significance of a High SD
Insulin deficiency (especially good with fasting blood glucose) Poor matching of calories (especially carbohydrates) with insulin Gi i mealtime insulin l Giving li i li late ( missing shots (or i i h 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 Dont over-treat the lows! Reduce carbs Pramlintide Lag times

Timing of Rapid-Acting Analog Insulin Injection Alters PPG in Type 1 Diabetes Mellitus
Insulin Lispro
288 252

BG Level (mg/d dL)

180 144 108 72 36 0 -30 0

BG Level (mg/d dL)

216

Injection-Meal Interval (minutes) 30 m 15 m 0m +15 m

Insulin Glulisine
288 252 216 180 144 108 72 36 0 -30 0

Injection-Meal Interval (minutes) 20 m 0m +20 m

8.6 kcal/kg breakfast

30 60 90 120 150 180 210 240 270 300

Standardized breakfast
30 60 90 120 150 180 210 240 270 300

Minutes

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

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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?

Mr. Henrys Download Statistics Summary (30 days)

Frequency of testing = Fasting mean/SD: AC lunch mean/SD: AC dinner mean/SD HS mean/SD: Overall:
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

3.2X/day 114 + 24 122 + 42 140 + 49 179 + 88 135 + 42

Teaching Point 4
Downloading of glucose data is extremely helpful to see patterns not otherwise noted for those checking g more than 2X/day. These downloads will become more accessible over the next few years with the use of tablets and smartphones

Mr. Jay Hawk

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.

Mr. Jay Hawk, cont

Glucose 435 mg/dL (24.1mM), all other electrolytes WNL except sodium of 133. HbA1C 14.0% (normal 4-6%) Ui k t Urine ketones: negative ti
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

Ms. O. Duck
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

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Mr. CO Interest
Mr. Interest, also called COI, 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

COI (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 therap;y

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?