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.
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 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
Change in A1c
ADA, 2012, abstracts/poster session
Change in Weight
ADA, 2012, abstracts/poster session
Prandial (Pre-meal)
Insulin
Injected Prandial Insulin
Rapid Acting
or
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)
SC administered
drug depot
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
Pharmacokinetic Results
• The three marketed rapid acting analog insulins have similar time
exposure profiles
Morrow et al. ADA oral presentation 2010
23
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
24
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 AnalogPH20 Demonstrated Throughout Study
Meal
% Reduction in
Glycemic Excursion
Breakfast
73% (p=.017)
Lunch
34% (p=.44)
Dinner
219% (p=.040)
Overall
82% (p=.0045)
Overall mean PPG change (90 minutes) from pre-meal baseline, routine SMBG monitoring throughout each treatment
phase.
Confidential
26
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?
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
Medtronic MiniMed Guardian® REAL-Time
Continuous Glucose Monitoring System
Diabetes Technology Explosion
CSII Reduces Incidents of Severe
Hypoglycaemia1/4
Severe Hypoglycaemic Episodes: CSII vs MDI
1
2
3
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
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:
p=0.004
Minutes per event
1. Alert Group
• Alerts On 50%
• Alerts Off 50%
2. Control Group
• Alerts Off
Period 1
Period 2
p=0.03
80
69.6
64.4
63.8
60
33.6
40
20
Alerts
off
Alerts
on
Alerts
off
Alerts
off
0
Alert Group
Control Group
CGM alerts improve glycemic control
1. Bode et al. 2004 Diab.Tech & Therapeutics 6(2): 105-113.
Sensor Report
The Road to
Closing the Loop
36
The Road to Closing the Loop
1.
2.
3.
4.
5.
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
• Suspends insulin infusion for a 2hour period
• All other sensor functions and
alerts remain operational during
insulin suspension
• Fictional illustration of Low Glucose Suspend function in
use
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
LGS – CareLinkTM Therapy Management Software Tracing
Introducing the MiniMed Paradigm® Veo™ System
A new era in diabetes management
• Closing the loop
– First device to offer sensor-driven adjustments to insulin delivery
• 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
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
Veo system: patient view
42
Examples of Successful Inductions
43
Effect of LGS on hypoglycemia
By means of %SG for individual users**
Reduction in severe
hypoglycemic blood glucose
levels is observed with LGS
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
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
44
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