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 insulinproducing cells ID: 647358
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Slide1
Type 1 Diabetes:2012 and Beyond
Tom Blevins MD
Texas Diabetes and Endocrinology
Austin, TexasSlide2Slide3
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.
2012Slide4
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.Slide5
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. Slide6
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) Slide7
“Ideal” Basal Insulin
The “ideal” longer acting insulin may be expected to Reduced variabilityLower 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.Slide8
Basal Insulins in DevelopmentSlide9
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 hoursSlide10
Insulin DegludecSlide11
Degludec: Basal-Bolus Type 1Slide12
LY2605541Slide13
Pharmacodynamic Profiles of LY2605541
Heise, et al, Poster ADA 2012Slide14
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 sessionSlide15
Change in A1c
ADA, 2012, abstracts/poster sessionSlide16
Change in Weight
ADA, 2012, abstracts/poster sessionSlide17
Prandial (Pre-meal) InsulinSlide18Slide19
Injected Prandial Insulin
Rapid Actingor
Very Rapid Acting
(Warp Speed?)Slide20
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 delaySlide21Slide22
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 (1/3
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 depotSlide23
Pharmacokinetic Results
The three marketed rapid acting analog insulins have similar time exposure profiles
Morrow et al. ADA oral presentation 2010Slide24
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 2010Slide25
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 Slide26
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)
ConfidentialSlide27
Artificial PancreasSlide28
Closed loop “automatic” systems (pump-sensor)Slide29
Is Hypoglycemia a Challenge?
Do some of your adults or children with diabetes suffer from:
Hypoglycaemia Unawareness?
Nocturnal Hypoglycaemia?
Or a fear of Hypoglycaemia?Slide30
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 Slide31
Diabetes Technology ExplosionSlide32
CSII Reduces Incidents of Severe Hypoglycaemia1/4
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
2
3
Severe Hypoglycaemic Episodes: CSII vs MDISlide33
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:
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.
Period 1
Period 2
Minutes per event
Alerts
off
Alerts
on
33.6
Alerts
off
Alerts
off
p
=0.004
p
=0.03Slide34Slide35
Sensor ReportSlide36
36
The Road to Closing the LoopSlide37
The Road to Closing the Loop
Low Glucose SuspendPredictive low glucoseHigh glucose bolus
Predictive high glucose bolus
True closed loopSlide38
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 suspensionSlide39
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 loopSlide40
LGS – CareLink
TM
Therapy Management Software
TracingSlide41
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 s
ensitivity 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
Slide42
Veo system: patient view Slide43
Examples of Successful InductionsSlide44
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 <= 80Slide45
Fictional illustration of alerts in useSlide46
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)Slide47
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.Slide48
“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 neededSlide49
Q and A