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1. 2 Accreditation and Designation of Credit The Network for Continuing Medical Education ( NCME) is accredited by the Accreditation Council for Continuing.

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Presentation on theme: "1. 2 Accreditation and Designation of Credit The Network for Continuing Medical Education ( NCME) is accredited by the Accreditation Council for Continuing."— Presentation transcript:

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2 2 Accreditation and Designation of Credit The Network for Continuing Medical Education ( NCME) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.

3 3 Disclosure Statement The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity.

4 Faculty Disclosure Curtis Triplitt, PharmD Texas Diabetes Institute Clinical Asst. Professor, Dept. of Medicine/ Div. of Diabetes, University of Texas Health Science Center at San Antonio Speakers Bureau- Amylin/Lilly for Byetta Consulting-Consulting Fees- Roche/Johnson & Johnson/ Novonordisk/ Takeda 4

5 5 Learning Objectives After taking part in this activity, participants should be able to: Recognize that postprandial glucose control involves multiple glucoregulatory hormones, including the beta-cell hormone amylin Describe the physiologic and clinical benefits of amylin- replacement therapy in insulin-requiring patients with diabetes Identify patients who are candidates for amylin-replacement therapy, and develop individualized treatment strategies using this therapy as an adjunct to insulin

6 6 Limitations of Intensified Insulin Therapy Added to Oral Therapy: 4-T Trial Type 2 Diabetes: Metformin + Sulfonylurea Failure Basal Insulin (n=234) Prandial Insulin (n=239) Biphasic Insulin (n=235) If A1C levels unacceptable on or after week 24, add second insulin Target glucose: mg/dL preprandial; mg/dL at 2 hours postprandial Investigators and patients were encouraged to vary suggested insulin doses, as clinically necessary, and amend the doses between visits Add 10 units of long acting at bedtime (73.6% of patients) Add 4-6 units of preprandial tid (81.6% of patients) Add 4-6 units of preprandial mid-day (67.7% of patients) Holman RR, et al. N Engl J Med. 2009;361:

7 7 Distribution of A1C Levels: 4-T Trial After 3 Years of Intensified Insulin Therapy Added to Metformin Adapted from Holman RR, et al. N Engl J Med. 2009;361: A1C, % Baseline Prandial Insulin (n=239) Basal Insulin (n=234) Biphasic Insulin (n=235) Above Normal Density Prandial Insulin 32.6% Basal Insulin 36.8% Biphasic Insulin 50.6% Patients (%) with A1C >7.0

8 Hypoglycemia by Treatment: 4-T Trial After 3 Years of Intensified Insulin Therapy Added to Metformin 8 Hypoglycemia (Grade 2 or 3), % Biphasic Insulin Prandial Insulin Basal Insulin Holman RR, et al. N Engl J Med. 2009;361: P=.03, prandial vs basal; P=.09, biphasic vs prandial; P=.56, biphasic vs basal; P=.09, overall comparison between 3 groups.

9 9 Holman RR, et al. N Engl J Med. 2009;361: Weight Gain by Treatment: 4-T Trial After 3 Years of Intensified Insulin Therapy Added to Metformin Mean Relative Change in Weight, kg P=.21, biphasic vs prandial; P=.005, biphasic vs basal; P<.001, prandial vs basal Biphasic Insulin Prandial Insulin Basal Insulin

10 10 Holman RR, et al. N Engl J Med. 2009;361: Daily Insulin Dose Required by Treatment: 4-T Trial After 3 Years of Intensified Insulin Therapy Added to Metformin Median Daily Insulin Dose, IU/kg a a P=.05, biphasic vs prandial; P<.001, biphasic vs basal; P=.07, prandial vs basal Biphasic Insulin Prandial Insulin Basal Insulin The median daily insulin dose per kg of body weight increased steadily during the second and third years of the study

11 11 Monnier L, et al. Diabetes Care. 2003;26: Postprandial Glucose Contribution to Diurnal Hyperglycemia Contribution, % A1C Range, % Postprandial Plasma Glucose > < Fasting Plasma Glucose

12 12 Meal Adapted with permission from Müller WA, et al. N Engl J Med. 1970;283: Insulin Deficiency and Glucagon Hypersecretion in Type 2 Diabetes Defects in diabetes Deficient insulin release Glucagon not suppressed (postprandially) Hyperglycemia Insulin, µU/mL Time, min Glucagon, pg/mL Glucose, mg/dL Control Patients (n=11) T2DM Patients (n=12)

13 13 Type 2 Diabetes: Postprandial Glucagon Not Corrected by Exogenous Insulin Adapted with permission from Unger RH, et al. N Engl J Med. 1971;285: Carbohydrate Meal U/mL pg/mL Glucagon Insulin Time, min Insulin Values Before Insulin Infusion Values After Insulin Infusion

14 14 Amylin Insulin Amylin 1,2 A neuroendocrine hormone deficient in diabetes 37-amino acid peptide first reported in 1987 Co-localized and co-secreted with insulin from pancreatic -cells Deficient in diabetes Not an incretin-mimetic 1.Unger RH, Foster DW. In: Wilson J, Foster D, eds. Williams Textbook of Endocrinology. 8th ed. Philadelphia: WB Saunders Co.; 1992: O'Brien TD, et al. Vet Pathol. 1993;30: Human amylin

15 15 Time After Sustacal ® Meal, min Plasma Amylin, pmol/L Meal T1DM (n=190) Insulin-using T2DM (n=27) Without diabetes (n=27) Amylin Is Co-Secreted With Insulin and Deficient in Diabetes Plasma Insulin, pmol/L Time, 24-h Meal Amylin Insulin Plasma Amylin, pmol/L Healthy male adults (n=6) Adapted with permission from Kruger DF, et al. Diabetes Educ. 1999;25: AMMidnight5 PM12 Noon

16 Amylin Helps Regulate Postprandial Gycemia By Multiple Mechanisms Enhances feeling of fullness at meals Slows inappropriately accelerated gastric emptying Decreases hepatic glucose output via suppression of postprandial pancreatic glucagon secretion 16 Young A. Adv Pharmacol. 2005;52:67-77.

17 17 Effect of Pramlintide on Postprandial Glucagon Type 1 Diabetes 2 Time, h Placebo Pramlintide Infusion of 25 µg/h pramlintide or placebo Insulin Meal Type 2 Diabetes, Late Stage 1 Time, h Plasma Glucagon, pg/mL Insulin Meal Infusion of 100 µg/h pramlintide or placebo Plasma Glucagon, pg/mL T2DM: AUC 1–4 h : P=.005. T1DM: AUC 1–5 h : P< Adapted with permission from Fineman M, et al. Horm Metab Res. 2002;34: Adapted with permission from Fineman M, et al. Metabolism. 2002;51: N=12N=9

18 18 Effect of Pramlintide on Postprandial Glucose Type 2 Diabetes 1 Type 1 Diabetes 2 1.Adapted with permission from Maggs DG, et al. Diabetes Metab Res Rev. 2004;20: Adapted with permission from Weyer C, et al. Diabetes Care. 2003;26: Time Relative to Meal and Pramlintide, h Plasma Glucose, mg/dL Mean (SE) Time Relative to Meal and Pramlintide, h Plasma Glucose, mg/dL Mean (SE) Placebo + Insulin Lispro Pramlintide 120 µg + Insulin Lispro Placebo + Insulin Lispro Pramlintide 60 µg + Insulin Lispro N=19 N=21 SE, standard error.

19 19 Type 1 diabetes patients (N=11) with usual insulin doses Crossover study Administered placebo or indicated pramlintide doses 15 minutes before ingestion of 99m Tc- labeled pancake Gastric emptying monitored by imaging Kong MF, et al. Diabetologia. 1998;41: Effect of Pramlintide on Gastric Emptying Gastric Contents Emptied Per Hour, % a a a P<.004 versus placebo Placebo30 µg Pramlintide 60 µg Pramlintide

20 Mean Total Caloric Intake, kcal Fat Carb Fat Protein Effect of Pramlintide on Caloric Intake -170 kcal (-16%) P<.02 Carb Fat Protein -202 kcal (-23%) P<.01 Patients With Type 2 Diabetes (N=11) Mean Total Caloric Intake, kcal Obese Patients Without Diabetes (N=15) Protein Placebo120 µg Pramlintide Placebo120 µg Pramlintide Adapted with permission from Chapman I, et al. Diabetologia. 2005;48:

21 21 Effects of Pramlintide at 26 Weeks in Patients With Type 1 Diabetes Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; Whitehouse FW, et al. Diabetes Care. 2002;25: Ratner R, et al. Diabet Med. 2004;21: kg -1.1 kg a Placebo + Insulin (n=538) 30 or 60 µg Pramlintide + Insulin (n=716) % a -0.43% A1C, % Insulin Doses, % Weight, kg +1.7% +2.5% +1.9% -3.6% Rapid/Short-Acting Long-Acting a P< Pooled Analysis of 3 Phase 3 Clinical Trials

22 22 Effects of Pramlintide at 26 Weeks in Patients with Type 2 Diabetes 1,2 Placebo + Insulin (n=284) 120 µg Pramlintide + Insulin (n=292) 1.Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; Hollander PA, et al. Diabetes Care. 2003;26: – A1C, % Insulin Doses, % Weight, kg -0.17% +0.2 kg a -1.5 kg 1.0 a -0.57% +6.5% +5.2% a -0.2% a -3.0% Rapid/Short-Acting Long-Acting a P< Pooled Analysis of 2 Phase 3 Clinical Trials

23 23 Effect of Pramlintide on Diurnal Glucose Excursions in Patients With Type 2 Diabetes Reproduced with permission from Karl D, et al. Diabetes Technol Ther. 2007;9: a a a a a a a Prebreakfast Postbreakfast Prelunch Postlunch Predinner Postdinner Bedtime Baseline (insulin alone) 6 Months (insulin + pramlintide) Mean (SE) Plasma Glucose, mg/dL N=166 at baseline; a P<.05; SE, standard error Clinical Practice Trial

24 24 Effects of Pramlintide at 6 Months in Patients With Type 2 Diabetes a P<.05 compared with baseline levels % a A1C, % -10.3% -4.2% -6.4% a a TotalBasalMealtime Insulin Use, % -2.8 kg a Weight, kg 120 µg Pramlintide + Insulin (N=166) Karl D, et al. Diabetes Technol Ther. 2007;9: Clinical Practice Trial

25 25 Pramlintide vs Rapid-Acting Insulin: Primary End Point Riddle M, et al. Diabetes Care. 2009;32: P<.018 Pramlintide n=56 Rapid-Acting Insulin n= Patients Achieving Composite End Point, % Composite end point = A1C 7.0%, no weight gain, and no severe hypoglycemia In Combination With Basal Insulin in Patients With Type 2 Diabetes

26 26 Reproduced with permission from Riddle M, et al. Diabetes Care. 2009;32: Pramlintide Rapid-Acting Insulin -1.3 ± 0.2% -1.1 ± 0.2% LS mean from baseline (LOCF) Week Mean (SE) A1C, % Pramlintide vs Rapid-Acting Insulin: A1C In Combination With Basal Insulin in Patients With Type 2 Diabetes LOCF, last observation carried forward; LS, least squares; SE, standard error.

27 27 Reproduced with permission from Riddle M, et al. Diabetes Care. 2009;32: Pramlintide Rapid-Acting Insulin -34 ± 6 mg/dL -31 ± 6 mg/dL Week Mean (SE) FPG, mg/dL Pramlintide vs Rapid-Acting Insulin: FPG In Combination With Basal Insulin in Patients With Type 2 Diabetes LS mean from baseline (LOCF) LOCF, last observation carried forward; LS, least squares; SE, standard error.

28 28 a P<.01 vs rapid-acting insulin; b P<.001 vs rapid-acting insulin. LOCF, last observation carried forward; LS, least squares; SE, standard error. Reproduced with permission from Riddle M, et al. Diabetes Care. 2009;32: Pramlintide Rapid-Acting Insulin a -0.0 ± 0.7 kg +4.7 ± 0.7 kg Week Mean (SE) Body Weight, kg b b b Pramlintide vs Rapid-Acting Insulin: Body Weight LS mean from baseline (LOCF) a In Combination With Basal Insulin in Patients With Type 2 Diabetes

29 29 N=28; Mean (standard error [SE]) change from baseline. Pramlintide + Premixed Insulin in Patients With Type 2 Diabetes A1C, % Daily Insulin Doses, % Weight, kg Pramlintide 120 µg + Premixed Insulin (70/30 or 75/25) PPG, mg/dL Lorenzi G, et al. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA. Abstract 2119-PO.

30 30 Pramlintide Safety and Tolerability Insulin-induced severe hypoglycemia –More common in type 1 diabetes than in type 2 diabetes –Risk reduced by appropriate patient selection, careful patient instruction, and insulin dose adjustments Nausea –Mostly mild to moderate; occurred more frequently during initiation and then decreased with time in most patients –More common in type 1 diabetes than in type 2 diabetes –Reduced by dose titration of pramlintide Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

31 31 Pramlintide Indications Pramlintide is given at mealtimes and is indicated for: Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

32 32 Pramlintide Patient Selection: Appropriate Pramlintide therapy should be considered only in patients with insulin-using type 2 or type 1 diabetes who fulfill the following criteria: Have failed to achieve adequate glycemic control despite individualized insulin management Are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by services of diabetes educators Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

33 33 Pramlintide Patient Selection: Inappropriate Exclude patients who meet any of the following criteria: Poor compliance with current insulin regimen Poor compliance with prescribed self-monitoring of blood glucose A1C >9.0% Recurrent severe hypoglycemia requiring assistance during past 6 months Hypoglycemia unawareness Confirmed diagnosis of gastroparesis Require the use of drugs that stimulate gastrointestinal motility Pediatric patients Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

34 34 Initiating Pramlintide in Type 2 Diabetes Start at 60 µg –Immediately before major meal/snack –Reduce mealtime insulin by 50% –Frequent self-monitoring of blood glucose –If no significant nausea for 3-7 days, increase pramlintide dose Increase pramlintide dose to 120 µg (maintenance dose) –If nausea occurs and persists, reduce to 60 µg –Once target dose achieved and nausea subsides, adjust insulin doses to optimize glycemic control Initiation 120 µg 60 µg Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

35 35 Initiating Pramlintide in Type 1 Diabetes Start 15 µg –Immediately before major meal/snack –Reduce mealtime insulin by 50% –Frequent self-monitoring of blood glucose –If no significant nausea for at least 3 days, increase pramlintide dose Increase dose in 15-µg increments every 3 days as tolerated to maximum of 60 µg (maintenance dose) –If nausea occurs and persists, reduce to previous dose –Once target dose achieved and nausea subsides, adjust insulin doses to optimize glycemic control 15 µg 30 µg 45 µg 60 µg Initiation Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

36 36 Administration Considerations Subcutaneous injection into abdomen or thigh –Arm not recommended because of variable absorption Do not mix with insulin –Can alter peak and action times of both Pramlintide and insulin should always be given as separate injections and at separate sites at least 2 inches apart –2 inches prevents inadvertent mixing at site Inject before each major meal or snack containing 250 kcal or 30 g of carbohydrate –Less carbohydrate may increase risk of hypoglycemia Symlin [package insert]. Amylin Pharmaceuticals, Inc; San Diego, CA; 2008.

37 37 Discussion Question What do you perceive are the primary reasons for patients discontinuing pramlintide?

38 38 Patients Primary Reasons for Discontinuing Pramlintide Did not lose weight Side effects (self-reported) Additional injections required Too expensive Dosing regimen too complicated Lack of effectiveness (self-reported) Education re: expectations 4 of 6 primary reasons for discontinuation can be addressed with additional education about realistic expectations, potentially assisting 57% of patients to continue treatment Patients, % N=127 Reproduced with permission from Lorenzi GM, et al. Clin Diabetes. 2011;29:17-24.

39 39 Patient Barriers Diabetes knowledge Knowledge of insulin therapy Frequency of blood glucose monitoring More frequent injections Expectations of medication Cost Fear of hypoglycemia Access to diabetes education

40 40 Discussion Question In your opinion, what are clinician barriers to the use of pramlintide?

41 41 Healthcare Team Barriers Access to diabetes education Understanding of mechanisms of insulin Time required to teach patients how to use pramlintide Perceived benefit, or lack of benefit Out-of-pocket cost to patient Requirement for prior authorization Increased injection frequency Belief that patients will not take Value of weight loss

42 42 Discussion Question How can patient barriers and healthcare team barriers be overcome?

43 43 Overcoming Barriers Samples Starter kits Patient support program Insurance support Start once daily with largest meal Add to biphasic insulin Basal-bolus use Use of continuous glucose monitoring

44 44 Patient Instructions: Hypoglycemia Precautions No pramlintide if no meal/snack No pramlintide before a snack used to treat hypoglycemia If quantity of food intake uncertain, consider: –Altered timing of insulin –Proactive insulin dose adjustment Patient education –Preventive actions –Symptom recognition and verification –Treatment

45 45 Patient Instructions: When to Call for Help Erratic or wide swings in blood glucose More frequent hypoglycemia, even if mild Any severe hypoglycemia Moderate or severe nausea Persistent nausea Vomiting Injection difficulties Any condition that may alter food intake

46 46 Current treatment regimen/history The patient is currently taking insulin glargine 80 units at 10:00 PM and rapid-acting insulin 20 units tid before meals Lunchtime injection is skipped on most days A1C: 8.8% Weight: 90 kg; height: 510; BMI: 28.3 kg/m 2 The patient has agreed to try pramlintide at dinner Case: 67-Year-Old African-American Man With Type 2 Diabetes for 12 Years

47 47 Discussion Questions When initiating pramlintide... When should the patient monitor his blood glucose? What are the patients blood glucose goals? How often would you increase the pramlintide dose? What would influence the pramlintide dose-titration schedule? How frequently would you follow up with the patient?

48 48 Insulin Adjustment Considerations: Avoiding Hypoglycemia Pramlintide should be taken with meals or snacks that contain at least 250 calories or 30 g of carbohydrate Titrating pramlintide with an appropriate decrease in insulin will help prevent hypoglycemia If hypoglycemia occurs, remember that the insulin dose, and not pramlintide, is the cause –Re-evaluate the dose of insulin and decrease it as needed The manufacturers directions focus on lowering the bolus insulin dose only; while most of the blood glucose–lowering effect involves postprandial blood glucose, it is important to also evaluate the basal insulin dose

49 49 Additional Insulin Adjustment Considerations If the basal insulin is greater than 50% of the total daily insulin, it may be necessary to lower the basal insulin rate as well while patients are increasing the pramlintide dose Patients who lose weight may also need a lower basal insulin rate Patients who take insulin are well aware of how their body responds to their insulin dosing; when pramlintide is added, they must rethink how their body will respond to their insulin Pramlintide works to reduce appetite; if patients are not sure how much they will consume, they may wish to hold their premeal bolus or, if they use an insulin pump, square-wave the bolus over several hours If the bolus is held, a blood glucose level should be taken 2-4 hours after the meal; if the blood glucose is elevated, a correction bolus (not a premeal bolus) can be administered

50 50 Initiating pramlintide Dinnertime premeal insulin is decreased by 30% Pramlintide is started at 60 µg minutes before dinner 2-h postprandial blood glucose ranges from mg/dL The patient reports mild nausea Case: 67-Year-Old African-American Man With Type 2 Diabetes for 12 Years

51 51 Considerations for Initiating Pramlintide: Minimizing Nausea There is no specific number of days that patients must stay on a particular dose of pramlintide; the manufacturer has provided guidelines, but the dose should be individualized based on the patients response In addition to mild premeal nausea that may occur as pramlintide is being titrated, patients may experience nausea if they eat beyond the drug-induced satiety Gradually titrating the pramlintide dose will minimize nausea; if nausea occurs, do not increase the pramlintide dose until the nausea subsides Patients must be instructed to pay attention to the feeling of fullness

52 52 At 1 week, he has experienced no nausea for 3 days Pramlintide is increased to 120 µg minutes before dinner and insulin is decreased an additional 20% No nausea with either dose No issues with hypoglycemia At 4 weeks The patient lost 3.2 kg 2-hour postprandial (dinner) blood glucose ranges from mg/dL Fasting blood glucose is mg/dL Predinner insulin is lowered an additional 20% Insulin glargine is decreased to 60 units Case: 67-Year-Old African-American Man With Type 2 Diabetes for 12 Years

53 53 The patient asked to use pramlintide at breakfast. How would you proceed with his regimen? Discussion Question

54 54 Breakfast premeal insulin is lowered 50% Pramlintide is started 60 µg; after 1 week, it is increased to 120 µg After breakfast, blood glucose is mg/dL; insulin is lowered an additional 20% Over the next 8 weeks, insulin glargine is lowered to 56 units Prebreakfast and predinner insulin is stopped Pramlintide is given 120 µg at breakfast and dinner; it is used at lunch on weekends Case: 67-Year-Old African-American Man With Type 2 Diabetes for 12 Years

55 55 At 3 months A1C: 7.6% Weight loss: -5.5 kg Insulin glargine: 56 units at bedtime Premeal insulin is stopped At 6 months A1C: 6.0% Weight loss: -9.1 kg Insulin glargine: 56 units at bedtime No premeal insulin Pramlintide 120 µg before meals tid Case: 67-Year-Old African-American Man With Type 2 Diabetes for 12 Years

56 56 Patient Outcome Bolus insulin by 100% Basal insulin by 20% A1C, %Weight, kgBMI, kg/m 2 Pre-pramlintide months months Case: 67-Year-Old African-American Man With Type 2 Diabetes for 12 Years

57 57 Additional Considerations for Pramlintide Use Pramlintide dosing does not need to be adjusted for physical activity Unopened pens of pramlintide should be kept in the refrigerator; opened and unused pens can be kept at room temperature for up to 28 days Patients who start pramlintide therapy need the support of a diabetes educator The time commitment needed to start a patient on pramlintide is similar to that of starting an insulin pump

58 58 Conclusions- Take home messages Pramlintide reduces postprandial hyperglucagonemia and hyperglycemia in patients with type 1 or type 2 diabetes Pramlintide also slows gastric emptying, reduces caloric intake, and reduces diurnal glucose excursions In clinical trials of patients with poorly controlled diabetes on insulin therapy, the addition of pramlintide was associated with significant reductions in –A1C (type 1 and type 2 diabetes) –Body weight (type 1 and type 2 diabetes) –Insulin use (type 2 diabetes; nonsignificant reductions in type 1 diabetes) Careful patient selection, patient instruction, and insulin dose adjustment are necessary for patients being considered for pramlintide therapy

59 59 Question-and-Answer Session

60 60 Thank you for participating!


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