Insulin regimens

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  • Slide 6-23 INSULIN TACTICS Twice-daily Split-mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times. Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care . 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews . 1995;3:308-334.
  • Study 1010 Study 1010 was a phase I, randomized, double-blind, 3-way crossover, euglycemic clamp study to evaluate the effect of obesity on the pharmacodynamic and pharmacokinetic behavior of glulisine, lispro, and regular human insulin The population included 18 obese individuals with increased abdominal tissue thickness determined by an MRI of abdominal subcutaneous fat layer The subjects acted as their own controls (crossover design) Subjects were given a single 0.3 U/kg dose of insulin subcutaneously in a crossover manner Results — Glulisine displays a rapid- and short-acting profile in obese individuals, which is more consistently maintained over the body mass index range of 30 kg/m 2 to 40 kg/m 2 and a range of subcutaneous fat thickness compared with lispro and regular human insulin Frick AD, Burger F, Scholtz H, Becker RHA. Time-action profile of insulin glulisine vs regular human insulin and insulin lispro in obese subjects. American Diabetes Association 64th Scientific Sessions. June 4-8, 2004; Orlando, Fla. Abstract 526.
  • Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
  • Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
  • Slide 6-6 TYPE 2 DIABETES…A PROGRESSIVE DISEASE Natural History of Type 2 Diabetes The natural history of type 2 diabetes shows the progressive emergence of the disorder. Well before diagnosis, patients may have had significant hyperglycemia for years, perhaps more than a decade. Patients with type 2 diabetes have altered islet  -cell function and impaired insulin action in varying degrees. Plasma glucose may rise above normal in early adulthood, and as age-related declines in  -cell function occur—together with less physical activity and increases in adipose tissue mass—plasma glucose continues to rise. By the time diabetes is diagnosed, plasma glucose may range from 180 to 220 mg/dL. It has been estimated that only about one third of the population has acceptable glycemic control by current standards. Based on the progressive nature of diabetes, complications that may take years to develop are often already present at the time of diagnosis. Riddle MC. Tactics for type II diabetes. Endocrinol Metab Clin North Am . 1997;26:659-677; Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapies of Diabetes Mellitus . St Louis, Mo: Mosby-Year Book Inc; 1998:108-116.
  • Slide 35 OAD Basal Insulin Therapy: Insulin Secretagogues or Sensitizers + Glargine at HS Based on advances in insulin therapy, future regimens for type 2 diabetes patients might include the use of an injectable, long-acting basal insulin analog in combination with oral agents or possibly with inhaled human insulin Addition of basal insulin glargine to a combination of oral agents can improve glycemic control, reducing glucotoxicity, which may in turn restore endogenous insulin response to SU and potentiate the effect of insulin sensitizers Alternatively, long-acting insulin glargine can provide a basal insulin profile to be associated in the future with prandial inhaled insulin, which mimics normal insulin effects in response to meals
  • Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
  • Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
  • Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
  • Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
  • Slide 35 OAD Basal Insulin Therapy: Insulin Secretagogues or Sensitizers + Glargine at HS Based on advances in insulin therapy, future regimens for type 2 diabetes patients might include the use of an injectable, long-acting basal insulin analog in combination with oral agents or possibly with inhaled human insulin Addition of basal insulin glargine to a combination of oral agents can improve glycemic control, reducing glucotoxicity, which may in turn restore endogenous insulin response to SU and potentiate the effect of insulin sensitizers Alternatively, long-acting insulin glargine can provide a basal insulin profile to be associated in the future with prandial inhaled insulin, which mimics normal insulin effects in response to meals
  • Over the 24-wk treatment period, A1C improved from 9.1% to 7.8% with morning insulin glargine, from 9.1% to 8.3% with bedtime NPH insulin, and from 9.1% to 8.1% with bedtime insulin glargine Improvement in A1C was more pronounced with morning insulin glargine than bedtime insulin glargine (p=0.008) or with NPH insulin (p<0.001) Results: Mean A1C Levels During Study Slide 10 Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:13:pages TBD
  • Slide 10 Mean A1C Concentrations During Study The forced-titration schedule of insulin glargine and NPH insulin produced a decline in mean A1C concentration, which reached a constant level after 18 weeks There were no between-treatment differences at end point (week 24) Mean A1C concentration was 6.96% for insulin glargine Mean A1C concentration was 6.97% for NPH insulin
  • Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
  • Objective : The exact contribution of postprandial and fasting glucose increments to overall hyperglycemia remain controversial. The discrepancies between the data published previously might be caused by the interference of several factors. To test the effects of overall glycemic control itself, the authors analyzed the diurnal glycemic profiles of type 2 diabetic patients investigated at different levels of HbA1c. Design and Methods – In 290 non-insulin and non-acarbose using patients with T2DM, plasma glucose (PG) concentrations were determined at fasting (8AM) and during postprandial and postabsorptive periods (at 11AM, 2PM and 5PM). The areas under the curve above fasting PG (FPG) concentration (AUC1) and >6.1 mmol/L (AUC2) were calculated for further evaluation of the relative contributions of postprandial PG (PPG) ([AUC1/AUC2] x 100 = %) and FPG ([AUC2-AUC1]/AUC2) x 100 = % increments to overall diurnal hyperglycemia. The data were compared over quintiles of A1c. Results – The relative contribution of PPG DECREASED progressively from the lowest (69.7%) to the highest quintile of A1c (30.5%, p<0.001 ), whereas the relative contribution of FPG INCREASED gradually with increasing levels of A1c: 30.3% in the lowest to 69.5% in the highest quintile (p<0.001). CONCLUSIONS: The relative contribution of PPG excursions is predominant in fairly controlled patients, whereas the contribution of FPG hyperglycemia increases gradually with diabetes worsening. These results could therefore provide a unifying explanation for the discrepancies as observed in previous studies. FIX FASTING FIRST!! “ Contributions of Fasting and Postprandial Plasma Glucose Increments to the Overall Diurnal Hyperglycemia of Type 2 Diabetic Patients” – Louis Monnier, MD; Helene Lapinski, MD; and Claude Colette, PhD. Diab Care 26:881-885, 2003.
  • Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
  • Mean insulin glargine dose remained unchanged (30 IU/d at baseline vs 31 IU/d endpoint) [Lankisch Abstract line 28-29]
  • At week 24, the A1C was significantly reduced in both the ALG and Carb Count groups ( P <0.0001) [Bergenstal Abstract line 18-19]
  • The ALG group had a higher mean dose of insulin glulisine than the Carb Count group (110.2 vs 94.3 U, respectively; P =0.04) [Bergenstal Abstract line 21-22]
  • Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
  • Slide 6-55 INSULIN TACTICS: THE FUTURE Oral Agents + Mealtime Inhaled Insulin Effect on HbA 1c The concept of inhaled insulin has been explored for those patients with type 2 diabetes who resist initiating insulin therapy because it requires injections. As a response to this resistance, a dry powder aerosol delivery system of human insulin has been developed. Weiss et al examined the ability of mealtime inhaled insulin to improve glycemic control in 69 subjects. Patients were randomized to a 3-month treatment period of either continued oral agents alone (sulfonylurea and/or metformin) or in combination with 1 or 2 puffs of inhaled insulin before meals. The inhaled insulin doses were titrated based on glucose testing 4 times daily. Patients continuing on oral agents alone showed little change in HbA 1c at 12 weeks (–0.13%), while those receiving the inhaled insulin in addition to the oral agents exhibited a marked improvement in HbA 1c (–2.28%). Weiss SR, Berger S, Cheng S, Kourides I, Landschulz W, Gelfand RA, for the Phase II Inhaled Insulin Study Group. Diabetes . 1999;48(suppl 1):A12.
  • In addition to HbA 1c - lowering effects, inhaled insulin consistently reduced fasting plasma glucose (FPG) levels to a significantly greater degree than SC insulin (as measured by 95% CIs). The baseline levels expressed in mg/dL are at the top of the bar and levels at end point are at the bottom. Values in parentheses are converted to mmol/L. Results from 3 different studies comparing inhaled insulin with SC insulin are shown on this slide. In the standard and intensive insulin therapy studies, the adjusted difference between inhaled insulin and SC insulin were - 25.17 (95% CI, - 43.39 to - 6.95) and - 39.53 (95% CI, - 57.50 to - 21.56), respectively. In the on insulin study, the adjusted difference was - 15.88 (95% CI, - 26.61 to - 5.15). 1,2 These reductions appear to be unrelated to the basal insulin dose administered the night before FPG measurement, and the mechanism for these changes is currently under investigation. Hollander P, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin in patients with type 2 diabetes: a 6 - month, randomized, comparative trial. Diabetes Care . In press. Data on file. Pfizer Inc, New York, NY.
  • Insulin regimens

    1. 1. Monday, July 16, 2012 1
    2. 2. Objectives1. Discuss the different types of insulin preparations available to manage types 1 and 2 diabetes2. Review the various insulin protocols and address appropriate patient selection for each3. Address how to design and adjust insulin regimensMonday, July 16, 2012 2
    3. 3. What Type of Insulins Are Available?Monday, July 16, 2012 3
    4. 4. Normal Pancreas ‘Bolus’ Insulin (Meal Associated)Insulin Effect Basal Insulin (~0.5-1.0 U/hr.) Insulin is released in response to varying blood glucose levelsMonday, July 16, 2012 and hypoglycemia does not occur 4
    5. 5. Basal vs Bolus InsulinBASAL INSULIN BOLUS INSULIN• Suppress hepatic glucose • Meal-associated CHO production (overnight and disposal intermeal) • Storage of nutrients• Prevent catabolism (lipid • Help suppress inter-meal and protein) hepatic glucose – Ketosis production – Unregulated amino acid release• Reduce glucolipotoxicityMonday, July 16, 2012 5
    6. 6. Insulin Profiles Regular (6–10 hr) NPH (10–20 hr)Plasma Insulin Levels Ultralente (~16–20 hr ) 0 2 4 6 8 10 12 14 16 18 20 22 24 Monday, July 16, 2012 Time (hr) 6 Rosenstock J. Clin Cornerstone. 2001;4:50-61.
    7. 7. The Diffusion Of InsulinMonday, July 16, 2012 Holleman F. NEJM 1997;337(3):176-83 7
    8. 8. Insulin Self Association SitesMonday, July 16, 2012 8
    9. 9. Newer Insulins ONSET PEAK DURATION MODIFCATION (hr) (hr) (hr) LISPRO β-chain Pro →Lys28 0.25-0.5 1-2 3-5 (Humalog) β-chain Lys →Pro29 ASPART β-chain Pro →Asp28 0.25-0.5 1-2 2-4 (NovoLog) GLULISINE β-chain Lys → 3 Asn Similar Simil ar Similar (Apidra) β-chain Lys → 29 Glu GLARGINE β-chain Asp → 21Gly 1 None 24 (Lantus) β-chain Arg31 /Arg32 DETEMIR β-chain Lys29 (Nε- 2 6-8 18 (Levemir) tetradecanoyl)des( β- 30 ) thrMonday,NPH 2012 Native July 16, insulin complexed 1-4 8-10 12-20 9 with protamine
    10. 10. Analog Insulin Profiles Aspart, Lispro, Glulisine (4–5 hr) Regular (6–10 hr) NPH (10–20 hr)Plasma Insulin Levels Ultralente (~16–20 hr ) Detemir ~18hr Glargine (~24 hr) 0 2 4 6 8 10 12 14 16 18 20 22 24 Monday, July 16, 2012 Time (hr) 10 Rosenstock J. Clin Cornerstone. 2001;4:50-61.
    11. 11. Rapid-Acting Analogs and RHI in Obese Subjects 6 Glulisine * Lispro GIR, mg.kg-1.min-1 5 * Regular human insulin 4 N=18 BMI=30 kg/m2 to 40 kg/m2 3 2 1 0 0 60 120 240 360 480 600 Time, minDosage=0.3 U/kg GIR=Glucose Infusion Rate * p< .05 GIR-t20% vs RHI and Lispro Monday, July 16, 2012 11Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.
    12. 12. Fatty Meals---Rapid Acting Insulin HYPERGLYCEMIA INSULIN ACTIVITY GLUCOSE LEVELS TIMEMonday, July 16, 2012 12
    13. 13. Effect of Premixing on Rapid- Acting Analog Properties Tmax 49-53 min Aspart 1,2 Tmax 2.4 hours 70/30 NovoLog Mix 3 Plasma Insulin Levels -60 0 60 120 180 240 300 360 420 480 540 Time (min)1. Hedman CA et al. Diabetes Care Monday, July 16, 20122001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 131999;55:199-201 3. Novo Nordisk, data on file
    14. 14. Effect of NPH on GIR mg/dl 90 mmol/l 5.0 80 4.5 GLUCOSE 70 Plasma Glucose INFUSION 4.0 RATE 4.0 24 PEN DOWN 20 3.0 µmol/Kg/min 16 mg/Kg/min 0.3 U/Kg NPH s.c. 2.0 MIX 12 1.0 8 0 4 PEN UP 0 Monday, July 16, 2012 0 1 2 3 4 5 6 7 8 9 14Lepore M. et al., unpublished data Time (hours)
    15. 15. Type 1 DiabetesMonday, July 16, 2012 15
    16. 16. Bolus vs Basal Insulin• Bolus insulins • Basal insulins – Regular – NPH – Humalog (lispro) – Lente – NovoLog (aspart) – Ultralente – Apidra (glulisine) – Lantus (glargine) – Levemir (detemir)L Combination insulins — 70/30 and 50/50 — Humalog mix (75/25 or NPL) — NovoLog mix (70/30 or NPA)Monday, July 16, 2012 16
    17. 17. Basic Insulin Regimen: Split- Mixed Regimen or Premix • Does not Endogenous insulin mimic normal Regular physiology NPH Hyperglycemia • Requires meal consistency • Snacking may result in weight gain • Hypo- and hyperglycemiaB L D HS BMonday, July 16, 2012 17
    18. 18. Basal-Bolus or Physiologic Insulin Therapy Endogenous insulin Bolus insulin Insulin Effect Basal insulin B L D HSAdapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Monday, permission 18Marcel Dekker, Inc; 2002:193
    19. 19. Case---History25 year old student comes to clinic for management of type 1 diabetes. He was diagnosed approximately 3 years ago and has been managed with twice daily NPH insulin and lispro. He is frustrated because his glucose values fluctuate considerably, and he is having multiple episodes of hypoglycemia.His most recent A1C returned 7.8%.Monday, July 16, 2012 19
    20. 20. Case---Continuous MonitoringMonday, July 16, 2012 20
    21. 21. Case Study--HistoryHis current insulin regimen consists of 16 U of NPH plus 5 to 15 U of lispro prior to breakfast and 12 U of NPH with a similar amount of lispro prior to supper. He would give correction doses of lispro prior to lunch, bedtime and occasionally at 2-4 AM. If he was ‘low’, he would eat carbohydrate and not take lispro.His home glucose log documented testing 4 to 5 times a day with values ranging from 40 to 500 mg/dl.How should his management be approached?Monday, July 16, 2012 21
    22. 22. Case Study--Approach• Set a reasonable goal for glycemic control – Initial goal was to avoid hypoglycemia (glucose targets 120-150 mg/dL)• Trouble-shoot the insulin regimen – Which type of insulin and which injection is doing what? – Good luck doing it with this patient!Monday, July 16, 2012 22
    23. 23. Case Study--Approach• Variables with injected insulin: – Type of insulin and site of injection – Type of food and gastric emptying – Remembering to take injections – Accuracy of HGM• Designing an insulin regimen – Think in terms of basal and bolusMonday, July 16, 2012 23
    24. 24. Case Study--Approach• We opted to use glargine as the basal insulin and lispro as the bolus insulin• Dose calculations: – TDD: 48 to 73 U – Basal (as NPH): 16+12=28 U CURRENT REGIMEN – Glargine: 28 x 0.8=22.4 U 16/10 and 12/10 (N/H) TDD≈48 U/day PLUS up to 25 U H/D Monday, July 16, 2012 24
    25. 25. Case Study--Approach• Usual insulin regimens are 50:50 or 60:40 basal:bolus – TDD: 48 to 73 U – Glargine: 22 U – Bolus: ~ 22 U (50:50 Rule) • Per meal 22/3= 7.3 U/meal• Designed regimen: Glargine 22 U/HS; lispro 7 U BEFORE EACH MAJOR MEAL Monday, July 16, 2012 25
    26. 26. Case Study--Approach• Correction doses (‘sliding scale’) – 1700 Rule (some modify this as the 1500 Rule or the 1800 Rule) – 1700/TDD = Expected amount of glucose lowering per unit of insulin• Our patient – 1700/44 = 38 ∴ 1 U insulin would lower his glucose 38 mg/dlMonday, July 16, 2012 26
    27. 27. Case Study--Approach• Our goal glucose is ~ 150 mg/dL• Our patient is instructed to: – Take 22 U glargine at bed time (or ~ 10:00 PM) – Start with 7 U of lispro before meals • For every 50 mg/dL glucose is above 150, add 1 U lispro or for every 50 below 150, subtract 1 U lispro – Have the patient monitor and adjust the regimen based upon results of HGMMonday, July 16, 2012 27
    28. 28. Carbohydrate Counting• There is no literature to document superiority of CHO counting – Estimation aids many patients with T1DM – Likely not effective in T2DM• Establishing insulin:carbohydrate ratio – [Correction factor] x 0.33 = CHO gm covered by 1 unit of insulin – Usual ratio is 10-15:1 – Adjust based upon 2 hour postprandial glucose valuesMonday, July 16, 2012 28
    29. 29. Clinical Secrets• Plan target glucose goals• Think in terms of basal and bolus insulin• Typical ratio of basal to bolus is 50:50 or 60:40• Correction doses are generally given before meals • 1700 Rule: 1700/TDD = Glucose lowering/unit insulin• Adjust basal insulin based upon FBS and bolus insulin based upon preprandial values Monday, July 16, 2012 29
    30. 30. Summary of Key Dose Concepts for Type 1 Diabetes Parameter Formula Usual RangeBasal insulin None (weight 12-24 U/dayrequirements based 0.2-0.5 U/kg)Bolus requirements Basal dose ÷ 3 or 5-10 U/meal(empiric) number of meals/dInsulin:CHO ratio CF x 0.33 ~15Correction factor 1700 ÷ TDD 30-50NOTE: These are approximations on starting a physiologic insulin regimen andmust beJuly 16, 2012based upon SMBG valuesMonday, adjusted 30
    31. 31. When Should Insulin Be Added In Patients With Type 2 Diabetes?Monday, July 16, 2012 31
    32. 32. Natural History of Type 2 Diabetes Postmeal Plasma glucose Glucose 126 mg/dL Fasting glucose Insulin resistance Relative β-Cell Function Insulin secretion −20 −10 0 10 20 30 Years of DiabetesAdapted from International Diabetes Center (IDC). Minneapolis, Minnesota. Monday, July 16, 2012 32
    33. 33. Therapy In Type 2 Diabetes: Estimated Improvement HbA1c FBG (mg/dL) Monotherapy Sulfonylurea 1.5% to 2% 50 to 60 Metformin 1% to 2% 50 to 60 Pioglitazone 0.6% to 1.9% 55 to 60 Rosiglitazone 0.7% to 1.8% 55 to 60 Glitazones (Troglit) 0.6% to 1.0% 20 to 40 Repaglinide 0.8% to 1.7% 30 to 40 Acarbose 0.5% to 1.0% 20 to 30 Sulfonylurea + Metformin ~1.7% ~65Combination Therapy Sulfonylurea + Pioglitazone ~1.2% ~50 Sulfonylurea + Troglitazone ~0.9% to 1.8% ~40 - 60 Sulfonylurea + Acarbose ~1.3% ~40 Repaglinide + Metformin ~1.4% ~40 Pioglitazone + Metformin ~0.7% ~40 Rosiglitazone + Metformin ~0.8% ~50 Insulin Therapy Monday, July 16, 2012 33 Oral Agents + Insulin Rx Open to Target Open to Target
    34. 34. Evolution of Treatment Strategies Pre-1995 2000 Current Diagnosis Diagnosis Diagnosis Monotherapy Dual Monotherapy Therapy SU Dual/Triple Basal TripleStop SU Therapy Insulin + Therapy OHA Stop OHA Stop SU Insulin Insulin Prandial and BasalMonday, July 16, 2012 34 Insulin + OHA
    35. 35. ADA/EASD Position Statement Diagnosis Lifestyle Intervention and Metformin No HbA1c ≥ 7% Yes Add Basal Insulin − Add Sulfonylurea − Add GLitazone − (most effective) (least expensive) ( no hypoglycemia)Check HbA 1c 16, 2012 3 months and act until HbA 1c is Check Monday, July every 35<7% Nathan DM et al. Diabetes Care. 2006;29:1963-1972
    36. 36. How Is Insulin Employed in Type 2 Diabetes? Different RegimensMonday, July 16, 2012 36
    37. 37. Basal Insulin Regimen Sensitizer Secretagogue Basal Insulin Insulin Effect BMonday, July 16, 2012 L D HS 37
    38. 38. Basic Insulin Regimen: Split- Mixed Regimen or Premix Endogenous insulin Regular NPH B L D HS BMonday, July 16, 2012 38
    39. 39. Basal-Plus Insulin Therapy Endogenous insulin Bolus insulin Insulin Effect Basal insulin B L D HSAdapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Monday, permission 39Marcel Dekker, Inc; 2002:193
    40. 40. Inhaled Bolus Insulin Therapy Endogenous insulin Bolus insulin Insulin Effect B L D HSAdapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Monday, permission 40Marcel Dekker, Inc; 2002:193
    41. 41. Basal-Bolus or Physiologic Insulin Therapy Endogenous insulin Bolus insulin Insulin Effect Basal insulin B L D HSAdapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Monday, permission 41Marcel Dekker, Inc; 2002:193
    42. 42. How Effective Are These Regimens?Monday, July 16, 2012 42
    43. 43. Basal Insulin Therapy Sensitizer Secretagogue Basal Insulin Insulin Effect BMonday, July 16, 2012 L D HS 43
    44. 44. Effects Of Basal Insulin □ HS NPH+Gly+Met r BID NPH • HS NPH+Metformin ∆ HS NPH+Glyburide Monday, July 16, 2012 44Yki-Järvinen et al; Ann Int Med 1999;130:389
    45. 45. Flexible Timing Of Glargine Compared With NPH Insulin 9.5 AM Glargine 9.0 HS Glargine HS NPH A1C (%) 8.5 8.3 8.0 8.1 7.8 * 7.5 0 4 8 12 16 20 24 Time (wk)* Decrease in A1C from baseline for AM Glargine: P<0.001 vs HS NPH and P=0.008 vs HSGlargine etJulyAnn Int Med 2003;138:952-959.Fritsche A al. 16, 2012 Monday, 45
    46. 46. Treat to Target Trial 9 Subjects were oral agent failures on SU alone or SU+metformin and basal Insulin glargineMean A1C (%) insulin was added and 8 NPH insulin aggressively titrated 7 Target A1C (%) ~60% of patients reached target 6 0 4 8 12 16 20 24 Monday, July 16, 2012 Weeks 46 Riddle et al. Diabetes Care. 2003;26:3080-3086
    47. 47. Achieving Glycemic Control (Detemir v Glargine) Detemir GlargineA1C at endpoint 7.16 % 7.12%(baseline adjusted)Insulin dose at 0.63 u/kg (0.02-3.96) 0.40 u/kgendpoint [0.43 u/kg (0.02-1.98) detemir QD (45% of pts.)] [0.85 u/kg (0.14-3.96) detemir BID (55% of pts.)Completion rate 80% 87%In-clinic FPG (mg/ 129.6 129.6dl) Monday, July 16, 2012 47 Rosenstock J et al. ADA 2006; Abstract 555-P
    48. 48. Do Algorithms and Basal Insulin Work? Community Center Start SU Without Algorithm Community University Center Add metformin Center + + Algorithm Start Algorithm insulinMonday, July 16, 2012 48 Fanning et al. Diabetes Care 2004;27:1638-1646
    49. 49. Gycemia Optimization Trial Proportion Severe HypoglycemiaGoal FPG Glargine Dose With A1C < Mean (Event/patient year) (mg/dl) (IU) 7.0% A1C (%) A1C < 7.0% A1C ≥ 7.0%120 (n=952) 59.2±37 31.5 7.58±1.1 0.02 0.02110 (n=974) 62.2±37 32.2 7.52±1.1 0.02 0.08100 (n=973) 69.6±41 37.5 7.41±1.1 0.04 0.0590 (n=950) 74.9±53 41.1 7.26±1.1 0.08 0.1280 (n=975) 78.1±43 44.3 7.32±1.2 0.11 0.19 Monday, July 16, 2012 49 Tannenberg et al. Insulin 2007;2 (suppl A):S10
    50. 50. Basic Insulin Regimen: Split- Mixed Regimen or Premix Endogenous insulin Regular NPH B L D HS BMonday, July 16, 2012 50
    51. 51. Aggressively Titrated Premix 70/30+Met+Pio Met+Pio Baseline A1C 8.1±1.0 7.9±0.9 EOS A1C 6.5±1.0 7.8±1.2 Percentage of Patients With A1C (EOS) <7.0% 76.3 24.1 ≤6.5 59.1 11.5 ≤6.0 33.3 2.3 ≤5.5 14.0 0 FPG (mg/dl) 130±50 162±41Monday, July 16, 2012 51 Raskin et al. Insulin 2007;2 (suppl A):S11
    52. 52. When and How Should Prandial Insulin Be Added?Monday, July 16, 2012 52
    53. 53. Contributions of FBG and PPG to Overall Glycemia PPG + FBG = HbA1c (%) 80 Contribution (%) 70 60 50 40 30 20 10 0 (<7.3) 1 2(7.3-8.4) 3(8.5-9.2) (9.3-10.2) 4 5(>10.2) PPG A1c Quintiles FPGMonday, July 16, 2012 53 Adapted from Monnier, Lapinski, Colette: Diab Care Mar 2003, pg 881
    54. 54. Basal-Plus Insulin Therapy Endogenous insulin Bolus insulin Insulin Effect Basal insulin B L D HSAdapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Monday, permission 54Marcel Dekker, Inc; 2002:193
    55. 55. Final Insulin Doses Basal-Plus Regimen ● 26 week study (safety 35 Basal Insulin Dose analysis) (N=158) ● Baseline A1C was 7.4% 30 31 and fell to 7.0%Insulin Dose (IU) 30 25 ● 26% achieved A1C < 6.5% 20 15 Rapid-Acting Dose 10 5 11 5 0 Baseline Endpoint Baseline Endpoint Monday, July 16, 2012 55 Abstracts of the 66th Scientific Sessions of the ADA. Diabetes. 2006; V(suppl X): XX. Abstract XX. Diabetes.
    56. 56. CHO Counting v Fixed Regimen Mean A1C Across Study Weeks 8.5 8.0 ALG A1C (%) Carb Count 7.5 7.0 6.5 0 2 6 12 18 24 Week Monday, July 16, 2012 56Abstracts of the 66th Scientific Sessions of the ADA. Diabetes. 2006; V(suppl X): XX. Abstract XX. Diabetes.
    57. 57. Insulin Doses Rapid-Acting Basal Insulin P=0.04 P<0.0001 120 100 110.2Dose (IU) 94.3 103.4 80 86.8 60 40 20 0 ALG Monday, July 16, 2012 Carb Count ALG Carb Count 57 Abstracts of the 66th Scientific Sessions of the ADA. Diabetes. 2006; V(suppl X): XX. Abstract XX. Diabetes.
    58. 58. Inhaled Bolus Insulin Therapy Endogenous insulin Bolus insulin Insulin Effect B L D HSAdapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Monday, permission 58Marcel Dekker, Inc; 2002:193
    59. 59. Inhaled Insulin (Exubera)• Uses powdered native 3mg Blister 3 0.15U/Kg (~10U Reg) human insulin (3) 1mg Blister – 1 and 3 mg blister packsMonday, July 16, 2012 59
    60. 60. Inhaled Insulin (Exubera) and OHA Oral Agents Alone Oral Agents + SU and/or Met Inhaled Insulin 10 9 −2.3% HbA1c (%) 8 * 7 6 5 Baseline Follow-up Baseline Follow-up (0) (12) (0) (12)*P < Monday, July 16, 2012 .001 Weeks 60Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
    61. 61. FPG: Exubera vs SC Insulin at End Point Type 1 DM Type 2 DM Standard Intensive On insulin 0 -5 194 203 201 209 152 158 Mean ∆ FPG (mg/dL) -10 207 149 -15 190 -20 132 -25 -30 -35 163 Exubera SC 167 -40Hollander PA, et al. Diabetes Care. 2004;27:2356-2362.Data on file. Monday, July 16, 2012 61
    62. 62. What Are the Side Effects of Exogenous Insulin?Monday, July 16, 2012 62
    63. 63. Hypoglycemia Severe insulin reactions per 100 patient-yr 0 20 40 60 80 100 120 DCCT 62 Type 1 SDIS 110 diabetes UKPDS 2.3 Type 2 VA CSDM 3 diabetes VA IIIP 7.8Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:Marcel Dekker, Inc.; 2002:193 Monday, July 16, 2012 63
    64. 64. Total Weight Gain and Total Insulin Dose 400 Total insulin 300 dose (U/d) 200 100 0 0 10 20 30 40 50 Monday, July 16, 2012 Total weight gain (lb) 64Adapted from Henry RR, et al. Diabetes Care. 1993;16:21-31.
    65. 65. Weight v Delta A1C Studies with Type 2 Diabetes Glargine NPH 2 7 7 Detemir1. Yki-Jarvinen Reduction in A1C (%)Diabetes Care 3 3 92000;23:11312. Rosenstock 1.5 8 9Diabetes Care 42001;24:631 3.Riddle Diabetes Care2003;26: 3079 4. Fritsche Ann Int 8 1 4Med 2003;138: 952 1 5.RaslovaDiab Res Clin Pract 2 1 5 52004;66:193 6. 0.5 2 2Haak Diab Obes Clin 6 6Pract 2005;7:567. Study 15308. Study 13379. Study 1373; 0Rosenstock, 2006 July 16, 2012 Monday, 1 2 3 4 65 Weight Gain (kg)
    66. 66. How Do The Various Approaches Compare?Monday, July 16, 2012 66
    67. 67. Comparison of Common Insulin Regimens*Variable Glargine* NPH1 Premix2,3 Detemir4Efficacy Insulin WorksHypoglycemia† 1.0 1.4X 2.5-5.0X 1.0Insulin Dose 1.0 1.0 1.5-2.0X 1.6-2.1XWeight Gain 1.0 1.0 1.5X 0.7-1.0X* Normalized to glargine; sponsored comparator trials† Confirmed hypoglycemia1 Riddle MC et al. Diabetes Care 2003;26:3080-30862 Janka HU et al. Diabetes Care 2005;28:254-2593 Raskin P et al. Diabetes Care 2005;28:260-2654 Monday, July 16, 2012 67 Rosenstock J et al. ADA 2006; Abstract 555-P
    68. 68. Conclusions• Adjunctive therapy with insulin in type 2 diabetes is both safe and effective• Instead of being the ‘last resort’, early insulin use is being encouraged by national organizations• Choice of insulin and/or regimen is dependent upon: – The patient – Pre-existing glycemic control – Duration of illnessMonday, July 16, 2012 68

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