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Using Insulin in the Primary Care Setting: Interactive Cases

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.

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Using Insulin in the Primary Care Setting: Interactive Cases

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  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. Glargine NPH Treat-to-Target TrialChange of A1c with systematic titration of basal insulin 9 8.68.6 Mean A1c % 8 7.57.4 7.17.1 6.96.9 6.96.9 7 58% ≤ 7% 6 0 4 8 12 16 20 24 Weeks of treatment Riddle MC et al. Diabetes Care 2003;26: 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 < 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 APOLLO3n = 174 T-T-T1n = 367 INSIGHT2n = 206 INITIATE4n = 58 • 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 • 5 Schreiber SA et al. DiabetesObes Metab 2007;9:31

  6. 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 56 47 -1.4 -1.6 34 -2.0 -2.6 8.5-8.9 ≥9.5 <8.0 <8.0 8.5-8.9 ≥9.5 9.0-9.4 8.0-8.4 8.0-8.4 9.0-9.4 75% of participants with baseline A1c <8% attained 7% Riddle MC et al. Diabetes 2009;58(Suppl 1): A125

  7. Baseline A1c does not affect hypoglycemia risk 2193 patients with 24 weeks systematically titrated glargine added to OAD Hypoglycemia requiring assistance Hypoglycemia confirmed <3.9 mmol/L (70 mg/dL) 50% 1.5% <8.0 8.5-8.9 ≥9.5 <8.0 8.5-8.9 ≥9.5 8.0-8.4 9.0-9.4 8.0-8.4 9.0-9.4 Titration of insulin was stopped at appropriate levels of risk Riddle MC et al. Diabetes 2009;58(Suppl 1): A125

  8. 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

  9. 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.

  10. 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 > 1.0 u/kg 1.0, 1.5, and 2.0 units/kg > 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

  11. 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

  12. Distribution of Skin Thickness Values (in mm)by Body Site and BMI • Small differences within each body site: obese higher (P<0.001) • 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

  13. 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

  14. 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

  15. 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)

  16. SMBG RESULTS

  17. NOW WHAT? • What to do with the glargine? • What to do with prandial insulin? • What to do with metformin, glipizide, and sitagliptin?

  18. 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!

  19. NOW WHAT TO SUGGEST?

  20. 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

  21. Which Patient Has More Variable Fasting Glucose Data? Joe: HbA1c = 6.5%; on liraglutide Mary: HbA1c = 6.5%; on metformin Mean = 123 mg% Mean = 123 mg% SD = 51 SD = 77

  22. 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

  23. Calculation To Determine SD Target SD X 2 < MEAN (T1DM) • Ideally SD X 3 < mean

  24. 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?

  25. Caveats of the SD • Need sufficient SMBG data • Low or high averages makes the 2XSD<mean rule irrelevant

  26. Other Tricks To Reduce GV • Enough testing • Don’t over-treat the lows! • Reduce carbs • Pramlintide/exenatide • Lag times

  27. Timing of Rapid-Acting Analog Insulin Injection Alters PPG in Type 1 Diabetes Mellitus Insulin Lispro Insulin Glulisine Injection-Meal Interval (minutes) 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 -30 0 30 60 90 120 150 180 210 240 270 300 -30 0 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.

  28. 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?

  29. Mr. Henry’s 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

  30. 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

  31. 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.

  32. 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

  33. 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)

  34. 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

  35. Teaching Point 6 • Pancreatectomized patients are glucagon deficient, are very insulin sensitive, and are prone to severe hypoglycemia

  36. 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

  37. 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

  38. 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

  39. 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?

  40. Teaching Point 8 • Insulin syringes come in 3 volumes: 1cc (100 units) ½ cc (50 units) and 0.3 cc (30 units)

  41. 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

  42. 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?

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

  44. Thank You!

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