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Non-Insulin Therapies for the Treatment of Type 1 Diabetes Irl B. Hirsch, MD University of Washington School of Medicine.

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Presentation on theme: "Non-Insulin Therapies for the Treatment of Type 1 Diabetes Irl B. Hirsch, MD University of Washington School of Medicine."— Presentation transcript:

1 Non-Insulin Therapies for the Treatment of Type 1 Diabetes Irl B. Hirsch, MD University of Washington School of Medicine

2 Initial Comments: Thinking Back Thinking back for the past 47 years, and looking at the history of diabetes for the past 90 years, do I see the future of diabetes as a glass half full or half empty? Answer: I see it as half full but Im not sure the FDA will allow me to put water in my glass

3 Yes, Im Frustrated

4 But I WONT Surrender to Science or Common Sense Which brings me to Therapy #1

5 Therapy #1 An extremely important non-insulin therapy Is not covered by insurance BUT is not very expensive Is good for everyone, even FDA officials What is it?

6 Exercise!

7 What We Know Improves diabetes control-makes one more sensitive to insulin Great for the entire cardiovascular system Helps maintain body weight You feel better! Reduces systemic inflammation Why is this important?

8 Inflammation in Type 1 DM The autoimmune attack of type 1 diabetes IS an inflammatory process on the beta-cells in the pancreas that make insulin Both small vessel (eyes/kidneys) and large vessel (heart, arteries to the head and leg) disease (blockage) is initiated by inflammatory activation So if exercises reduces inflammation, could there be any benefits with beta-cell preservation or complications?

9 But What If You Are Not A Mouse? Exp Diabetes Res 2011: epub Sept 2011

10 We Dont Know…BUT Several research presentations (not published to my knowledge) showing more active children had longer beta-cell function My anecdotal experience is exercise prolongs the honeymoon period

11 Case Presentation I started following a 40 year-old man in 1991 who was diagnosed with diabetic kidney disease, with serum creatinine of 2.0 mg/dL (about 50% of normal function) Besides starting a pump and improving his control (A1C %), he started a RIGOROUS exercise program-mountain climbing, riding his bike to work, etc In 2011, 20 years later, his creatinine is 2.0 mg/dL

12 OMG Thats not supposed to happen!

13 My Belief Glucose control, exercise, healthy diet-all contributed to his lack of progression of his kidney disease My advice: start the exercise programs early…stay active!

14 Therapy #2 AMYLIN A hormone co-secreted with insulin from the beta-cells in the pancreas For those who make a little insulin, they make a little amylin For those who make no insulin, they make no amylin

15 What Does Amylin Do? 1. It slows the movement of food from the stomach to the rest of the gut 2. It turns off glucagon, usually high in type 1 diabetes, and not needed when you eat Glucagon: causes the liver to make glucose (and suppresses the liver from storing glucose) Can also worsen resistance at the muscle In many, amylin reduces appetite

16 Does Amylin Work in Type 1 Diabetes? YES Generic name = pramlintide Trade name = Symlin® As expected: Symlin has not been evaluated for pediatric patients (package insert)

17 Pramlintide Improves Postprandial Glucose Evaluable; Mean (SE); Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18; Weyer C, et al. Diabetes Care 2003; 26: ; Pramlintide Acetate Prescribing Information, Time Relative to Meal and Pramlintide (min) Plasma Glucose (mg/dL) Plasma Glucose (mg/dL) Lispro Insulin Pramlintide 60 g + Lispro Insulin Regular Insulin Pramlintide 60 g + Regular Insulin Type 1 Diabetes

18 No Symlin dose titration during initiation (fixed dose) No insulin dose reduction at Symlin initiation Placebo Pramlintide Type 1 Diabetes Combined Pivotals Symlin® Clinical Effects Placebo Pramlintide Type 1 Diabetes Combined Pivotals Insulin Use (%) A1C (%) Weight (kg) Short- Acting Long- Acting

19 ** P <0.01; P < for changes from baseline; Hermann K, et al. Presented at ADA, 71 st Scientific Sessions; 2011; San Diego, CA (1065-P) Does Symlin® Work in Insulin Pump-Treated Patients in a Real-Life Clinical Practice Study?

20 My Thinking About Symlin® Therapy Amylin is co-secreted with insulin We currently administer Symlin® as a prandial hormone only What would happen if pramlintide was administered in a basal-bolus fashion? Amylin is co-secreted with insulin We currently administer Symlin® as a prandial hormone only What would happen if pramlintide was administered in a basal-bolus fashion? Continuous Subcutaneous Pramlintide Infusion = CSPI

21 CSPI: Proof of Concept 13 type 1 adolescent patients (age = 17 years, BMI = 22 kg/m 2, HbA1c = 7.4%) Cross-over study CSII with dual-wave bolus of insulin CSII + CSPI with dual-wave bolus of insulin and pram Results: 20% reduction of insulin dose, 26% reduction in postprandial glucose, reduction in glucagon levels 13 type 1 adolescent patients (age = 17 years, BMI = 22 kg/m 2, HbA1c = 7.4%) Cross-over study CSII with dual-wave bolus of insulin CSII + CSPI with dual-wave bolus of insulin and pram Results: 20% reduction of insulin dose, 26% reduction in postprandial glucose, reduction in glucagon levels JCEM 2009:94, 1608

22 CSPI: Proof of Concept JCEM 2009:94, 1608 Simultaneous continuous sc pramlintide and insulin infusion has the potential of improving glucose concentration by way of physiological replacement

23 So Why Cant We Infuse Symlin® in an Insulin Pump? THE GOOD NEWS

24 JDRF and Amylin Partner to Investigate Co-Formulating Two Hormones for Treatment of Type 1 Diabetes May 10, 2011 PRESS RELEASE

25 THERAPY #3 Incretin hormones Hormones from the gut which are secreted in response to oral but not intravenous glucose Responsible for reducing blood glucose spikes GLP-1 = Glucagon-like Peptide-1

26 GLP-1 Modes of Action in Man GLP-1 is secreted from the L-cells in the jejunum and ileum GLP-1 is secreted from the L-cells in the jejunum and ileum This in turn… Stimulates insulin secretion Suppresses glucagon secretion Slows gastric emptying Long term effects demonstrated in animals… Increases beta-cell cell mass and maintains beta-cell efficiency Reduces food intake Upon ingestion of food… Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:

27 Why Would This Be Helpful In Type 1 Diabetes? Could GLP-1 analogues, with similar mechanisms as amylin (other than insulin secretion), help A1C in type 1 DM? Could GLP-1 analogues improve beta cell function in newly diagnosed type 1 DM? As of today, we have two GLP-1 analogues Byetta, injected twice daily Victoza, injected once daily (Bydureon, awaiting FDA approval)

28 Byetta and Type 1 DM Minimal literature My guess: tried off label Beta cell preservation One trial-didnt help

29 Victoza and Type 1 DM Immediate reports of improvements in A1C and weight. THIS is what we are all seeing around the world with Victoza

30 Eur J Endocrinol 2011;165:77-84 OBERVATIONAL STUDY: Minimal scientific rigor

31 What About A Controlled Study? Randomized to + or – Victoza A1c reduced in both groups getting Victoza (6.6 to 6.4% and 7.5 to 7.0%). No change in non-Victoza group 2 of the 10 patients still making insulin could STOP their insulin on Victoza Honeymoon+Victoza No c-peptide+Victoza No Victoza > 180 < 70 Diabetes Care 2011;34:

32 GLP-1: Where I Think This Is Going A 41-year-old woman, 25 years with type 1 diabetes, BMI 36 kg/m 2, A1C 7.9% on insulin pump therapy s me about Victoza… Yo Doc, just an Oh, wow! moment for you. Started the 1.2 dose. Had cereal for dinner. Way bad, I know. Normally, I would have gone over 200 for a few hours no matter how much insulin I bolused. I never went over 130. Never. Insurance covers it. Have a super-dee- duper weekend.

33 Case Study: A 36-Year-Old with Type 1 Diabetes Type 1 diabetes for 1.5 years Started on metformin by the primary care provider, then put on liraglutide (Victoza) in April 2010 with an A1C of 6.6% Presents to me in September 2010

34 A1C = 5.2%

35 My Thoughts… The longer GLP-1 agonists may do better with type 1 DM than the shorter-acting drugs More impact on both fasting and postprandial glucose Better tolerated than Symlin Most exciting is early data on beta-cell preservation Recall: obesity is a new problem for type 1 DM too-not so 20+ years ago What is needed: large clinical trials In the meantime: dont expect insurance coverage in Western Washington (poor coverage in type 2 diabetes!)

36 What about blocking the enzyme that breaks down GLP-1?

37 Adapted from Deacon CF, et al. Diabetes. 1995;44: GLP-1 Secretion and Inactivation Intestinal GLP-1 release GLP-1 (7-36) active Mixed meal GLP-1 (9-36) inactive (>80% of pool) DPP-4 t ½ = 1 to 2 min

38 Inhibition of DPP-4 Increases Active GLP-1 GLP-1 (9-36) inactive Intestinal GLP-1 release Mixed meal GLP-1 (7-36) active DPP-4 Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. DPP-4 inhibitor

39 Several DPP-4s Available for Type 2 Diabetes Sitagliptin = Januvia Saxagliptin = Onglyza Linagliptin = Tradjenta What about a DPP-4 inhibitor for type 1 DM?

40 Therapy #4: Sitagliptin (Januvia) 20 patients, 8-week study Small but significant improvements in blood glucose A1C decreased by 0.3% Time between mg/dL increased No change in weight Larger, longer studies required Diabetic Medicine 2011:28:

41 Therapy #5: What About Bile-Acid Sequestrants for the Treatment of Type 1 DM? Bile acid sequestrants have been available for decades for the treatment of high cholesterol (hypercholesterolemia) Cholestyramine (Questran); colestipol (Colestid); colesevelam (Welchol) The newest of these drugs, Welchol, is also approved to treat type 2 DM-it lower A1C on average by 0.5% Mechanism not known What about a bile-acid sequestrant for type 1 DM?

42 Mean + (SEM) LDL in the Control and Colesevelam Treated Groups: N=40 Type 1 DM 10% drop in LDL in the Rx 4, 8, and 12 Wks P=0.02P=0.01P= Baseline4 Weeks8 Weeks12 Weeks Visit LDL-C mg/dL PlaceboColesevelam Garg et al, Diabetes Obesity and Metabolism, 2011

43 What About A1C? After 12 weeks, no significant reduction in A1C My take: study under-powered to show a reduction as the effect is real but small Garg et al, Diabetes Obesity and Metabolism, 2011

44 How Might Bile Acid Sequestrants Lower Glucose?

45 GLP-1 mean (±SEM) AUC GLP-1 AUC (pg/ml x min) Time (minutes) p=0.13 p=0.01 p=0.03 p=0.01 p=0.02 Placebo Colesevelam Garg et al, Diabetes Obesity and Metabolism, 2011

46 Bile Acid Sequestrants: What I See With huge use of statins, we rarely use these agents However, when statins not tolerated I see an obvious reduction in A1C levels in most patients My take: more studies in type 1 DM needed Reasonable alternative for over 40 year old patients who require statins and can tolerate the huge pills (or gritty powder)

47 Therapy #6 Raise you hand if you know what prolactin is Raise your hand if you know what bromocriptine is

48 Bromocriptine Prolactin is the hormone responsible for lactation and bromocriptine lowers prolactin levels What in the world does this have to do with diabetes?

49 Bromocriptine and Diabetes Mechanism isnt clear, but bromocriptine (Cycloset) improves diabetes control in type 2 diabetes A1C is generally reduced by 0.5% So what? In the one cardiovascular disease trial, bromocriptine lowered event rate

50 Therapy #7: Case 1 Case: 31 year-old man diagnosed with type 1 diabetes at the age of 3 months. Frequent severe hypoglycemia for many years Which non-insulin therapy should be considered?

51 Neonatal Diabetes One of several gene mutations impairing normal insulin secretion Infants usually quite ill, often DKA, always prior to 6 months of age, usually before 3 months of age Gene mutations can be tested at Childrens Hospital No need for insulin-treated with sulfonylureas

52 Case 2 21 year-old woman presents with type 1 DM diagnosed at age 14. Two brothers, a sister, and her mother and maternal aunt all were diagnosed with diabetes at the same time. What should our patient be treated with?

53 Maturity Onset Diabetes of Youth MODY Hepatic Nuclear Factor 1α MODY (MODY-3) Most common type of MODY (60%) Usually presents in adolescence or 20s Most often confused with T1DM In first few years, can achieve good control with sulfonylurea

54 Sulfonylureas Stimulate insulin secretion Used for the treated of type 2 DM since the 1950s Glyburide, glipizide, glmeperide the most common ones used

55 My Main Message Today: Dont Over- React to Your Childs A1C First, its an imperfect test

56 5% 97 (76-120) 6% 126 ( ) 7% 154 ( ) 8% 183 ( ) 9% 212 ( ) 10% 249 ( ) 11% 269 ( ) 12% 298 ( ) Average Glucose vs. A1C A1C AG mg/dL (95% CI) Diabetes Care 31: , 2008 What this means is someone with an A1C of 8% could have a lower mean glucose than someone else with an A1C of 7%!

57 Risk for Sustained DR in Conventional and Intensive Treatment: How the Controversy Started Conventional Adapted from Diabetes 44: , % Rate Per Patient Year 10% 9% 8% 7% Time During Study (Years) Mean HbA1c Risk for Sustained DR in Subgroups of the DCCT Intensive Rate Per Patient Year 9% 8% 7% Time During Study (Years) Mean HbA1c But in 2008 we were told this analysis was a statistical artifact

58 Fast Forward: adolescents stratified over 4 time periods DR assessed with fundus photography DOES THIS LOOK FAMILIAR? Diabetes Care 2011;34:

59 DR, MDI/CSII, A1C in 4 Time Periods Diabetes Care 2011;34: DR for CSII vs MDI: OR = 0.52 (95% CI ), p = 0.07

60 The Bottom Line A1C is important, but not as important as many thought in the past A1C only explains 11% of progression of diabetic retinopathy-few appreciate this fact More data continue to suggest HOW the A1C got to be what it is may be important-not just the number itself!

61 Conclusions There are many possible agents to be used in addition to insulin for the treatment of type 1 diabetes These agents are rarely used in pediatrics (T1D Exchange data) Exercise is the big exception! Mechanisms of these agents often are not clear, yet much excitement about beta-cell health with GLP-1 agonists A1C is important, but perhaps A1C quality is important too

62 Conclusion What goes through my mind with each patient: Make sure it is type 1 DM!

63 Thank You


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