Type 1 Diabetes:2012 and Beyond Tom Blevins MD Texas Diabetes and Endocrinology Austin, Texas
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
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.
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.
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)
“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.
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
Pharmacodynamic Profiles of LY2605541 Heise, et al, Poster ADA 2012
Better Glycemic Control and Weight Loss with the Novel Long-Acting Basal InsulinLY2605541 Compared with Insulin Glargine in Patients with Type 1 DiabetesJulio Rosenstock, Richard M. Bergenstal, Thomas Blevins, Linda A. Morrow, Melvin J. Prince, YongmingQu,VikramP. Sinha, Daniel C. Howey, Scott J.Jacober ADA, 2012, abstracts/poster session
Change in A1c ADA, 2012, abstracts/poster session
Change in Weight ADA, 2012, abstracts/poster session
Injected Prandial InsulinRapid Actingor Very Rapid Acting (Warp Speed?)
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
Hyaluronin and Hyaluronidase • Hyaluronan (hyaluronic acid) Structure/Function • Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydratepolymer that is part of the extracellular matrix • 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 (1/3rd 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 SC administered drug depot rHuPH20 disperses SC administered drugs
Pharmacokinetic Results • The three marketed rapid acting analog insulins have similar time exposure profiles Morrow et al. ADA oral presentation 2010
Pharmacokinetic Results • Faster In (Primary Endpoint): • With rHuPH20 insulin exposure in the 1st hour was 191%, 229%, and 246% of control for glulisine, lispro and aspart, respectively(all P< 0.0001) • 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) Morrow et al. ADA oral presentation 2010
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
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. Confidential
Is Hypoglycemia a Challenge? • Do some of your adults or children with diabetes suffer from: • Hypoglycaemia Unawareness? • Nocturnal Hypoglycaemia? • Or a fear of Hypoglycaemia?
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
2 3 1 CSII Reduces Incidents of Severe Hypoglycaemia1/4 Severe Hypoglycaemic Episodes: CSII vs MDI 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
Period 1 Period 2 p=0.004 p=0.03 33.6 Minutes per event Alerts off Alerts off Alerts off Alerts on CGM Alerts Reduce Duration of Hypoglycaemic Excursions1 • 71 Type 1 patients wore sensors over a 12-day period • Multi-Center RCT where patients were randomised to: • Alert Group • Alerts On 50% • Alerts Off 50% • Control Group • Alerts Off CGM alerts improve glycemic control 1. Bode et al. 2004 Diab.Tech & Therapeutics 6(2): 105-113.
The Road to Closing the Loop • Low Glucose Suspend • Predictive low glucose • High glucose bolus • Predictive high glucose bolus • True closed loop
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
Low Glucose Suspend is the first component of the closed loop • Reduces the severity of hypoglycemia • Complements the CGM alerts • Provides an additional safety measure for an unresponsive patient
Introducing the MiniMed Paradigm® Veo™ SystemA 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 benefits1 • CGM alerts • Give early warnings of glycaemic excursions • Reduce the duration of hypoglycaemic excursions2 • Improved sensor sensitivity in the hypoglycaemic range • Closing the loop • First device to offer sensor-driven adjustments to insulin delivery 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 2. Bode B., et al. Diabetes Technology and Therapeutics. Volume 6, Number 2, 2004
Effect of LGS on hypoglycemia • Reduction in severe hypoglycemic blood glucose levels is observed with LGS Fig. Comparison of low sensor BG when LGS is OFF vs. ON Percent time SG <= 50 Percent time SG <= 80 **”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
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)
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.
“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