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Type 1 Diabetes: 2012 and Beyond. Tom Blevins MD Texas Diabetes and Endocrinology Austin, Texas. Stem Cell Breakthrough . - PowerPoint PPT Presentation
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Type 1 Diabetes:2012 and Beyond
Tom Blevins MDTexas 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.
Basal Insulins in Development
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
Insulin Degludec
Degludec: Basal-Bolus Type 1
LY2605541
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 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
Change in A1c
ADA, 2012, abstracts/poster session
Change in Weight
ADA, 2012, abstracts/poster session
Prandial (Pre-meal) Insulin
Injected Prandial Insulin
Rapid 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 carbohydrate polymer 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
rHuPH20 disperses SC administered drugs
SC administered drug depot
2323
Pharmacokinetic Results
• The three marketed rapid acting analog insulins have similar time exposure profiles
Morrow et al. ADA oral presentation 2010
2424
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 1st 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
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
2626
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
Breakfast 73% (p=.017)
Lunch 34% (p=.44)
Dinner 219% (p=.040)
Overall 82% (p=.0045)
Confidential
Artificial Pancreas
Closed loop “automatic” systems (pump-sensor)
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
CSII Reduces Incidents of Severe Hypoglycaemia1/4
1 Rudolph JW, Hirsch IB. Endocrine Pract 2002: 8; 401 – 4052 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 2 3
Severe Hypoglycaemic Episodes: CSII vs MDI
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:
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 1Period 2
Min
utes
per
eve
nt 69.664.4 63.8
0
20
40
60
80
Alert Group Control Group
Alertsoff
Alerts on
33.6
Alertsoff
Alertsoff
p=0.004 p=0.03
Sensor Report
36
The Road to Closing the Loop
The Road to Closing the Loop
1. Low Glucose Suspend2. Predictive low glucose3. High glucose bolus4. Predictive high glucose bolus5. 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
• 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
LGS – CareLinkTM Therapy Management Software Tracing
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
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
Veo system: patient view
43
Examples of Successful Inductions
44
Effect of LGS on hypoglycemia
By means of %SG for individual users**
LGS Off LGS On p
Mean 151.34 156.04 0.050
STD 60.07 54.84 0.028
%SG<50 1.33 0.92 0.001%SG<60 3.58 2.63 0.140
%SG<70 6.73 5.48 0.433
%SG<80 11.39 10.05 0.866
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 <= 50 Percent time SG <= 80
Fictional illustration of alerts in use
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
Q and A
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