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Non-Insulin Therapies for the Treatment of Type 1 Diabetes

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

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Non-Insulin Therapies for the Treatment of Type 1 Diabetes

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  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 I’m not sure the FDA will allow me to put water in my glass

  3. Yes, I’m Frustrated

  4. But I WON’T 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 Don’t 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 5.9-6.2%), 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 • That’s 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 Type 1 Diabetes Lispro Insulin Pramlintide 60 g + Lispro Insulin 300 250 Plasma Glucose (mg/dL) 200 150 100 0 60 120 180 240 Regular Insulin Pramlintide 60 g + Regular Insulin 300 250 Plasma Glucose (mg/dL) 200 150 100 0 60 120 180 240 Time Relative to Meal and Pramlintide (min) Evaluable; Mean (SE); Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18; Weyer C, et al. Diabetes Care 2003; 26:3074-3079; Pramlintide Acetate Prescribing Information, 2005

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

  19. Does Symlin® Work in Insulin Pump-Treated Patients in a “Real-Life” Clinical Practice Study? ** P <0.01; †P <0.0001 for changes from baseline; Hermann K, et al. Presented at ADA, 71st Scientific Sessions; 2011; San Diego, CA (1065-P)

  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? Continuous Subcutaneous Pramlintide Infusion = CSPI

  21. CSPI: Proof of Concept • 13 type 1 adolescent patients (age = 17 years, BMI = 22 kg/m2, 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 “Simultaneous continuous sc pramlintide and insulin infusion has the potential of improving glucose concentration by way of physiological replacement” JCEM 2009:94, 1608

  23. So Why Can’t We Infuse Symlin® in an Insulin Pump? THE GOOD NEWS

  24. PRESS RELEASE JDRF and Amylin Partner to Investigate Co-Formulating Two Hormones for Treatment of Type 1 Diabetes May 10, 2011 http://www.jdrf.org/index.cfm?page_id=115726

  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. Upon ingestion of food… GLP-1 Modes of Action in Man • Stimulates insulin secretion • Suppresses glucagon secretion • Slows gastric emptying GLP-1 is secreted from the L-cells in the jejunum and ileum • Reduces food intake Long term effectsdemonstrated in animals… This in turn… • Increases beta-cell cell mass and maintains beta-cell efficiency Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

  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-didn’t 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. OBERVATIONAL STUDY: Minimal scientific rigor Eur J Endocrinol 2011;165:77-84

  31. What About A “Controlled Study”? “Honeymoon+Victoza” 70-180 70-180 • 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 < 70 No Victoza 70-180 70-180 > 180 No c-peptide+Victoza 70-180 70-180 Diabetes Care 2011;34:1463-1468

  32. GLP-1: Where I Think This Is Going • A 41-year-old woman, 25 years with type 1 diabetes, BMI 36 kg/m2, A1C 7.9% on insulin pump therapy emails 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-Oldwith 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: don’t expect insurance coverage in Western Washington (poor coverage in type 2 diabetes!)

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

  37. t½ = 1 to 2 min DPP-4 GLP-1 (9-36) inactive (>80% of pool) GLP-1 Secretion and Inactivation Mixed meal Intestinal GLP-1 release GLP-1 (7-36) active Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

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

  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 80-140 mg/dL increased • No change in weight • Larger, longer studies required Diabetic Medicine 2011:28:1176-81

  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. Placebo Colesevelam Mean + (SEM) LDL in the Control and Colesevelam Treated Groups: N=40 Type 1 DM 140.0 130.0 P=0.02 P=0.01 P=0.003 120.0 110.0 LDL-C mg/dL 100.0 90.0 80.0 128.8 108.0 128.6 95.7 128.0 97.7 125.4 98.3 70.0 Baseline 4 Weeks 8 Weeks 12 Weeks Visit ≥ 10% drop in LDL in the Rx group @ 4, 8, and 12 Wks 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 3500 Placebo Colesevelam 3000 p=0.02 2500 2000 p=0.03 p=0.01 p=0.01 1500 GLP-1 AUC (pg/ml x min) 1000 p=0.13 500 0 0 60 120 180 240 -500 Time (minutes) -1000 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 isn’t clear, but bromocriptine (Cycloset) improves diabetes control in type 2 diabetes • A1C is generally reduced by 0.5% • So what? • In the one 3000+ 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?

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