Presentation on theme: "Non-Insulin Therapies for the Treatment of Type 1 Diabetes"— Presentation transcript:
1 Non-Insulin Therapies for the Treatment of Type 1 Diabetes Irl B. Hirsch, MDUniversity 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
7 What We KnowImproves diabetes control-makes one more sensitive to insulinGreat for the entire cardiovascular systemHelps maintain body weightYou feel better!Reduces systemic inflammationWhy 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 insulinBoth small vessel (eyes/kidneys) and large vessel (heart, arteries to the head and leg) disease (blockage) is initiated by inflammatory activationSo 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…BUTSeveral research presentations (not published to my knowledge) showing more active children had longer beta-cell functionMy anecdotal experience is exercise prolongs the “honeymoon period”
11 Case PresentationI 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, etcIn 2011, 20 years later, his creatinine is 2.0 mg/dL
13 My BeliefGlucose control, exercise, healthy diet-all contributed to his lack of progression of his kidney diseaseMy advice: start the exercise programs early…stay active!
14 Therapy #2AMYLINA hormone co-secreted with insulin from the beta-cells in the pancreasFor those who make a little insulin, they make a little amylinFor 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 gut2. It “turns off” glucagon, usually high in type 1 diabetes, and not needed when you eatGlucagon: causes the liver to make glucose (and suppresses the liver from storing glucose)Can also worsen resistance at the muscleIn many, amylin reduces appetite
16 Does Amylin Work in Type 1 Diabetes? YESGeneric name = pramlintideTrade name = Symlin®As expected: “Symlin has not been evaluated for pediatric patients” (package insert)
17 Pramlintide Improves Postprandial Glucose Type 1 Diabetes10015020025030060120180240Time Relative to Meal and Pramlintide (min)Plasma Glucose (mg/dL)Plasma Glucose(mg/dL)Lispro InsulinPramlintide 60 g + Lispro InsulinRegular InsulinPramlintide 60 g + Regular InsulinEvaluable; Mean (SE); Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18; Weyer C, et al. Diabetes Care 2003; 26: ; Pramlintide Acetate Prescribing Information, 2005
18 Symlin® Clinical Effects Type 1 Diabetes Combined PivotalsType 1 Diabetes Combined PivotalsPlaceboPramlintidePlaceboPramlintide Insulin Use (%) A1C (%) Weight (kg)Short-ActingLong-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 < 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 insulinWe currently administer Symlin® as a prandial hormone onlyWhat would happen if pramlintide was administered in a “basal-bolus” fashion?Continuous Subcutaneous Pramlintide Infusion =CSPI
21 CSPI: Proof of Concept13 type 1 adolescent patients (age = 17 years, BMI = 22 kg/m2, HbA1c = 7.4%)Cross-over studyCSII with “dual-wave bolus” of insulinCSII + CSPI with “dual-wave bolus” of insulin and pramResults: 20% reduction of insulin dose, 26% reduction in postprandial glucose, reduction in glucagon levelsJCEM 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 http://www.jdrf.org/index.cfm?page_id=115726 JDRF and Amylin Partner to Investigate Co-Formulating Two Hormones for Treatment of Type 1 DiabetesMay 10, 2011
25 THERAPY #3 Incretin hormones Hormones from the gut which are secreted in response to oral but not intravenous glucoseResponsible for reducing blood glucose spikesGLP-1 = Glucagon-like Peptide-1
26 GLP-1 Modes of Action in Man Upon ingestion of food…Stimulates insulin secretionSuppresses glucagon secretionSlows gastric emptyingGLP-1 is secretedfrom the L-cellsin the jejunumand ileumReduces food intakeThis in turn…Long term effects demonstrated in animals…Increases beta-cell cell mass and maintains beta-cell efficiencyDrucker 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 analoguesByetta, injected twice dailyVictoza, injected once daily(Bydureon, awaiting FDA approval)
28 Byetta and Type 1 DM Minimal literature My guess: tried “off label” Beta cell preservationOne trial-didn’t help
29 Victoza and Type 1 DMImmediate reports of improvements in A1C and weight.THIS is what we are all seeing around the world with Victoza
31 What About A “Controlled Study”? “Honeymoon+Victoza”70-18070-180< 70No Victoza70-18070-180> 180Randomized to + or – VictozaA1c reduced in both groups getting Victoza (6.6 to 6.4% and 7.5 to 7.0%). No change in non-Victoza group2 of the 10 patients still making insulin could STOP their insulin on VictozaNo c-peptide+Victoza70-18070-180Diabetes 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/m2, 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 yearsStarted 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
35 My Thoughts…The longer GLP-1 agonists may do better with type 1 DM than the shorter-acting drugsMore impact on both fasting and postprandial glucoseBetter tolerated than SymlinMost exciting is early data on beta-cell preservationRecall: obesity is a new problem for type 1 DM too-not so 20+ years agoWhat is needed: large clinical trialsIn 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 GLP-1 Secretion and Inactivation Mixed mealIntestinalGLP-1releaseGLP-1 (9-36)inactive(>80% of pool)DPP-4t½ = 1 to 2 minGLP-1 (7-36)activeAdapted from Deacon CF, et al. Diabetes. 1995;44:
38 Inhibition of DPP-4 Increases Active GLP-1 Mixed mealIntestinalGLP-1releaseGLP-1 (7-36)activeDPP-4DPP-4 inhibitorGLP-1 (9-36)inactiveAdapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
39 Several DPP-4s Available for Type 2 Diabetes Sitagliptin = JanuviaSaxagliptin = OnglyzaLinagliptin = TradjentaWhat about a DPP-4 inhibitor for type 1 DM?
40 Therapy #4: Sitagliptin (Januvia) 20 patients, 8-week studySmall but significant improvements in blood glucoseA1C decreased by 0.3%Time between mg/dL increasedNo change in weightLarger, longer studies requiredDiabetic 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 knownWhat 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 140.0130.0P=0.02P=0.01P=0.003120.0110.0LDL-C mg/dL100.090.080.0128.8108.0128.695.7128.097.7125.498.370.0Baseline4 Weeks8 Weeks12 WeeksVisitPlaceboColesevelam≥ 10% drop in LDL in the Rx 4, 8, and 12 WksGarg 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 smallGarg et al, Diabetes Obesity and Metabolism, 2011
44 How Might Bile Acid Sequestrants Lower Glucose?
45 Garg et al, Diabetes Obesity and Metabolism, 2011 GLP-1 mean (±SEM) AUC35003000PlaceboColesevelamp=0.0225002000p=0.03p=0.01GLP-1 AUC (pg/ml x min)1500p=0.011000p=0.13500-50060120180240Time (minutes)-1000Garg et al, Diabetes Obesity and Metabolism, 2011
46 Bile Acid Sequestrants: What I See With huge use of statins, we rarely use these agentsHowever, when statins not tolerated I see an obvious reduction in A1C levels in most patientsMy take: more studies in type 1 DM neededReasonable 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 BromocriptineProlactin is the hormone responsible for lactation and bromocriptine lowers prolactin levelsWhat 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 diabetesA1C is generally reduced by 0.5%So what?In the one cardiovascular disease trial, bromocriptine lowered event rate
50 Therapy #7: Case 1Case: 31 year-old man diagnosed with type 1 diabetes at the age of 3 months. Frequent severe hypoglycemia for many yearsWhich non-insulin therapy should be considered?
51 Neonatal DiabetesOne of several gene mutations impairing normal insulin secretionInfants usually quite ill, often DKA, always prior to 6 months of age, usually before 3 months of ageGene mutations can be tested at Children’s HospitalNo need for insulin-treated with sulfonylureas
52 Case 221 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 20’sMost often confused with T1DMIn first few years, can achieve good control with sulfonylurea
54 Sulfonylureas Stimulate insulin secretion Used for the treated of type 2 DM since the 1950sGlyburide, glipizide, glmeperide the most common ones used
55 My Main Message Today: Don’t Over-React to Your Child’s A1C First, it’s an imperfect test
56 Average Glucose vs. A1C A1C AG mg/dL (95% CI) 5% 97 (76-120) 5% (76-120)6% 126 ( )7% 154 ( )8% 183 ( )9% 212 ( )10% 249 ( )11% ( )12% 298 ( )What this means is someone with an A1C of 8% could have a lower mean glucose than someone else with an A1C of 7%!Diabetes Care 31: , 2008
57 But in 2008 we were told this analysis was a “statistical artifact” Risk for Sustained DR in Conventional and Intensive Treatment: How the Controversy StartedRisk for Sustained DR in Subgroups of the DCCT242016128411%10%9%Mean HbA1cConventionalBut in 2008 we were told this analysis was a “statistical artifact”Rate Per Patient Year8%7%Time During Study (Years)IntensiveRate Per Patient Year9%8%7%Time During Study (Years)2420161284Mean HbA1cAdapted from Diabetes 44: , 1995
58 DOES THIS LOOK FAMILIAR? Fast Forward: 20111604 adolescents stratified over 4 time periodsDR assessed with fundus photographyDOES THIS LOOK FAMILIAR?Diabetes Care 2011;34:
59 DR, MDI/CSII, A1C in 4 Time Periods DR for CSII vs MDI: OR = 0.52 (95% CI ), p = 0.07Diabetes Care 2011;34:
60 The Bottom LineA1C is important, but not as important as many thought in the pastA1C only explains 11% of progression of diabetic retinopathy-few appreciate this factMore data continue to suggest HOW the A1C got to be what it is may be important-not just the number itself!
61 ConclusionsThere are many possible agents to be used in addition to insulin for the treatment of type 1 diabetesThese 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 agonistsA1C is important, but perhaps “A1C quality” is important too
62 Conclusion Make sure it is type 1 DM! What goes through my mind with each patient:Make sure it is type 1 DM!