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Type 1 Diabetes: 2012 and Beyond Tom Blevins MD Texas Diabetes and Endocrinology Austin, Texas.

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Presentation on theme: "Type 1 Diabetes: 2012 and Beyond Tom Blevins MD Texas Diabetes and Endocrinology Austin, Texas."— Presentation transcript:

1 Type 1 Diabetes: 2012 and Beyond Tom Blevins MD Texas Diabetes and Endocrinology Austin, Texas


3 Stem Cell Breakthrough In a breakthrough that signifies a move toward a cure for type 1 diabetes, Australian researchers have identified stem cells in the pancreas that can be turned into insulin-producing cells.... Identified and isolated stem cells from the adult pancreas, and then developed a way to coax them into insulin-producing cells that can secrete insulin in response to glucose. 2012

4 BCG In the study, six insulin-dependent adults with type 1 diabetes received either two doses of BCG or two fake vaccinations. In the three patients who received the vaccine: – "Bad" anti-insulin T cells began dying off. – New "good" regulatory T cells increased. – There were signs of new, albeit temporary, insulin production from pancreatic beta cells. The vaccine was safe.

5 Vitamin D Deficiency Linked to Type 1 Diabetes (Nov, 2012) — A study led by researchers from the University of California, San Diego School of Medicine has found a correlation between vitamin D3 serum levels and subsequent incidence of Type 1 diabetes. The six-year study of blood levels of nearly 2,000 individuals suggests a preventive role for vitamin D3 in this disease.

6 Quest to prolong the action of insulin 1930’s-- development of protamine zinc insulin Lente, NPH, and ultralente were developed as suspensions to prolong action by delaying absorption Glargine and detemir were developed to prolong subcutaneous absorption by altering amino acid structure (glargine) or adding fatty acylated side chains (detemir)

7 “Ideal” Basal Insulin The “ideal” longer acting insulin may be expected to – Reduced variability – Lower risk of hypoglycemia, – Reduce the need for twice-daily injections – Provide minimal peak activity – Restore physiologic distribution of the 2-fold portal to systemic insulin levels Subcutaneous systemic absorption results in similar portal and systemic levels With current insulins, reduced hepatic insulin action must be balanced with excess peripheral insulin action to maintain glucose homeostasis.

8 Basal Insulins in Development

9 Insulin Degludec-Novel Basal Insulin Forms a depot of soluble multi-hexamers at the injection site Half-life of ~25 hours and a consistent glucose-lowering effect of >42 hours

10 Insulin Degludec

11 Degludec: Basal-Bolus Type 1

12 LY2605541

13 Pharmacodynamic Profiles of LY2605541 Heise, et al, Poster ADA 2012

14 Better Glycemic Control and Weight Loss with the Novel Long-Acting Basal Insulin LY2605541 Compared with Insulin Glargine in Patients with Type 1 Diabetes Julio Rosenstock, Richard M. Bergenstal, Thomas Blevins, Linda A. Morrow, Melvin J. Prince, Yongming Qu,Vikram P. Sinha, Daniel C. Howey, Scott J.Jacober ADA, 2012, abstracts/poster session

15 Change in A1c ADA, 2012, abstracts/poster session

16 Change in Weight ADA, 2012, abstracts/poster session

17 Prandial (Pre-meal) Insulin


19 Injected Prandial Insulin Rapid Acting or Very Rapid Acting (Warp Speed?)

20 Do We Need Ultrafast Insulin? Current analog insulin is slower than the physiologic prandial insulin response of healthy individuals –Typical time to peak insulin concentration is 45-60 minutes for healthy subjects vs. 60-100 minutes for analog prandial insulin Tail of insulin action is longer than physiologic response and leads to 3- 6 hour post meal hypoglycemia (including nocturnal hypoglycemia) Prandial control is elusive for even “well-controlled” patients –Majority of patients fail to achieve Post-Prandial Glucose (PPG) goals Current analog insulin requires approximately 15-20 minutes meal delay


22 Hyaluronin and Hyaluronidase Hyaluronan (hyaluronic acid) Structure/Function Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrixgoocarbohydratepolymer Large (Mega Dalton), repeating sugar polymer found in interstitial tissues Forms barrier to bulk fluid flow in interstitial space Human body turns over more than 5 grams/day (1/3 rd of total body pool) Hyaluronidase Mechanism of Action Catalyzes the rapid depolymerization of hyaluronan Locally-acting, transient removal of the hyaluronan barrier to enhance the dispersion of coinjected drugs Rapid dispersion enhances insulin dissociation kinetics and accelerated absorption into the systemic circulation rHuPH20 disperses SC administered drugs SC administered drug depot

23 23 Pharmacokinetic Results The three marketed rapid acting analog insulins have similar time exposure profiles Morrow et al. ADA oral presentation 2010

24 24 Pharmacokinetic Results Faster Out: – Insulin exposure after 2 hours decreased by 43%, 54%, and 57% for PH20 coinjection with glulisine, lispro and aspart, respectively (all P < 0.0001) Faster In (Primary Endpoint): – With rHuPH20 insulin exposure in the 1 st hour was 191%, 229%, and 246% of control for glulisine, lispro and aspart, respectively (all P < 0.0001) Morrow et al. ADA oral presentation 2010

25 Human Hyaluronidase + Rapid Analog Insulin (RAI) Improves Postprandial Glycemic Control in Type 1 Diabetes Compared to Insulin Lispro Alone IRL B. HIRSCH, JAY S SKYLER, SATISH GARG, THOMAS BLEVINS, DANIEL E VAUGHN, DOUGLAS B MUCHMORE University of Washington, Seattle, WA; University of Miami, Miami, FL; University of Colorado Denver, Aurora, CO; Texas Diabetes and Endocrinology, Austin, TX; Halozyme Therapeutics, San Diego, CA Hirsch et al, ADA 2012 Poster

26 26 T1DM: Improved Prandial Control with Analog- PH20 Demonstrated Throughout Study Overall mean PPG change (90 minutes) from pre-meal baseline, routine SMBG monitoring throughout each treatment phase. Meal % Reduction in Glycemic Excursion Breakfast73% (p=.017) Lunch34% (p=.44) Dinner219% (p=.040) Overall82% (p=.0045) Confidential

27 Artificial Pancreas

28 Closed loop “automatic” systems (pump-sensor )

29 Is Hypoglycemia a Challenge? Do some of your adults or children with diabetes suffer from: –Hypoglycaemia Unawareness? –Nocturnal Hypoglycaemia? –Or a fear of Hypoglycaemia?

30 Medtronic MiniMed Guardian ® REAL-Time Continuous Glucose Monitoring System How to Address this Challenge? Current Therapy Options –CSII vs MDI –Continuous Glucose Monitoring (CGM) Advanced Therapy Options –Sensor-augmented Pumps –Automatic Insulin Shut-off Mechanism

31 Diabetes Technology Explosion

32 CSII Reduces Incidents of Severe Hypoglycaemia 1/4 1 Rudolph JW, Hirsch IB. Endocrine Pract 2002: 8; 401 – 405 2 Bode, BW et al., Diabetes Care 1996, 19:325-7. 3 Boland, EA et al., Diabetes Care 1999, 22:1779 - 84. 4 Pickup JC & Sutton, AJ. Diabet Med 2008;25:765-774 1 23 Severe Hypoglycaemic Episodes: CSII vs MDI

33 CGM Alerts Reduce Duration of Hypoglycaemic Excursions 1 71 Type 1 patients wore sensors over a 12-day period Multi-Center RCT where patients were randomised to: 1.Alert Group Alerts On 50% Alerts Off 50% 2.Control Group Alerts Off CGM alerts improve glycemic control 1. Bode et al. 2004 Diab.Tech & Therapeutics 6(2): 105-113. Period 1 Period 2 Minutes per event Alerts off Alerts on 33.6 Alerts off Alerts off p=0.004p=0.03


35 Sensor Report

36 36 The Road to Closing the Loop

37 1.Low Glucose Suspend 2.Predictive low glucose 3.High glucose bolus 4.Predictive high glucose bolus 5.True closed loop

38 How Does Low Glucose Suspend Work? User settable: On/Off Range: Trigger at <50 mg/dl Fictional illustration of Low Glucose Suspend function in use Suspends insulin infusion for a 2- hour period All other sensor functions and alerts remain operational during insulin suspension

39 Reduces the severity of hypoglycemia Complements the CGM alerts Provides an additional safety measure for an unresponsive patient Low Glucose Suspend is the first component of the closed loop

40 LGS – CareLink TM Therapy Management Software Tracing

41 Introducing the MiniMed Paradigm ® Veo ™ System A new era in diabetes management Greater protection from severe hypoglycaemia –Automatic insulin shut-off mechanism – Low Glucose Suspend (LGS) Greater protection from glycaemic excursions –CGM-ready insulin pump Combined CSII and CGM offer clinical benefits 1 –CGM alerts Give early warnings of glycaemic excursions Reduce the duration of hypoglycaemic excursions 2 –Improved sensor sensitivity in the hypoglycaemic range Closing the loop –First device to offer sensor-driven adjustments to insulin delivery 2. Bode B., et al. Diabetes Technology and Therapeutics. Volume 6, Number 2, 2004 1. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008;25:765-774

42 42 Veo system: patient view

43 43 Examples of Successful Inductions

44 44 Effect of LGS on hypoglycemia By means of %SG for individual users** LGS OffLGS Onp Mean151.34156.040.050 STD60.0754.84 0.028 %SG<501.330.920.001 %SG<603.582.630.140 %SG<706.735.480.433 %SG<8011.3910.050.866 Reduction in severe hypoglycemic blood glucose levels is observed with LGS Fig. Comparison of low sensor BG when LGS is OFF vs. ON **”Characterization of the Low Glucose Suspend Feature of the Medtronic Paradigm Veo Insulin Pump and Events Preceding its Activation”. To be presented by Dr. Fran Kaufman at the ADA conference 2011 Percent time SG <= 50Percent time SG <= 80

45 Fictional illustration of alerts in use

46 Studies Done at Here in Austin at Texas Diabetes and Endocrinology Basal Insulin – Degludec – Basal insulin lispro (BIL) Rapid, pre-meal insulin (warp speed) – Halozyme – Biodel Insulin pump-LGS (low glucose suspend)

47 Studies- ongoing or coming up for Type 1’s Sanofi U300- Lantus pen – Concentrated insulin, lower volume – 3 units for every 1 traditional unit Halozyme- Insulin pump with very rapid acting insulin Eli Lily BIL basal insulin flex dosing – Given in the am or pm-flat profile Liraglutide in Type 1’s – The agent that lowers glucose and glucagon with weight loss in Type 2 diabetes Novo Degludec – Long acting, basal insulin with flat profile.

48 “Smart Insulin” “Smart Insulin” works via competitive binding – insulin (orange lines), attached to a sugar group (orange hexagons), binds with a sugar-binding molecule (blue circle) in solution. – When glucose (blue hexagons) in the body is high, it competes with insulin to bind to the sugar-binding molecules, displacing insulin and releasing it into the bloodstream as needed

49 Q and A

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