Non-Insulin Therapies for the
Treatment of Type 1 Diabetes
Irl B. Hirsch, MD
University of Washington School of Medicine
Initial Comments: Thinking Back
 Thinking back for the past 47 years, and looking at
the history of diabetes for the past 90 years, do I
see the future of diabetes as a glass half full or half
empty?
Answer: I see it as half full
but I’m not sure the FDA
will allow me to put water
in my glass
Yes, I’m Frustrated
But I WON’T Surrender to Science or
Common Sense
Which
brings me to
Therapy #1
Therapy #1




An extremely important non-insulin therapy
Is not covered by insurance
BUT is not very expensive
Is good for everyone, even FDA officials
What is it?
Exercise!
What We Know
 Improves diabetes control-makes one more
sensitive to insulin
 Great for the entire cardiovascular system
 Helps maintain body weight
 You feel better!
 Reduces systemic inflammation
 Why is this important?
Inflammation in Type 1 DM
 The autoimmune attack of type 1 diabetes IS
an inflammatory process on the beta-cells in
the pancreas that make insulin
 Both small vessel (eyes/kidneys) and large
vessel (heart, arteries to the head and leg)
disease (blockage) is initiated by
inflammatory activation
So if exercises reduces inflammation, could there be any
benefits with beta-cell preservation or complications?
But What If You Are Not A Mouse?
Exp Diabetes Res 2011: epub Sept 2011
We Don’t Know…BUT
 Several research presentations
(not published to my knowledge)
showing more active children
had longer beta-cell function
 My anecdotal experience is
exercise prolongs the
“honeymoon period”
Case Presentation
 I started following a 40 year-old man in 1991 who
was diagnosed with diabetic kidney disease, with
serum creatinine of 2.0 mg/dL (about 50% of
normal function)
 Besides starting a pump and improving his control
(A1C 5.9-6.2%), he started a RIGOROUS exercise
program-mountain climbing, riding his bike to
work, etc
 In 2011, 20 years later, his creatinine is 2.0 mg/dL
OMG
 That’s not supposed to happen!
My Belief
 Glucose control, exercise, healthy diet-all
contributed to his lack of progression of his
kidney disease
 My advice: start the exercise programs
early…stay active!
Therapy #2
 AMYLIN
 A hormone co-secreted with insulin from
the beta-cells in the pancreas
 For those who make a little insulin, they
make a little amylin
 For those who make no insulin, they make
no amylin
What Does Amylin Do?
 1. It slows the movement of food from the stomach
to the rest of the gut
 2. It “turns off” glucagon, usually high in type 1
diabetes, and not needed when you eat
 Glucagon: causes the liver to make glucose (and
suppresses the liver from storing glucose)
 Can also worsen resistance at the muscle
 In many, amylin reduces appetite
Does Amylin Work in Type 1
Diabetes?




YES
Generic name = pramlintide
Trade name = Symlin®
As expected: “Symlin has not been
evaluated for pediatric patients” (package
insert)
Pramlintide Improves Postprandial Glucose
Plasma Glucose
(mg/dL)
Type 1 Diabetes
Lispro Insulin
Pramlintide 60 g + Lispro Insulin
300
250
200
150
100
Plasma Glucose
(mg/dL)
0
60
120
180
240
Regular Insulin
Pramlintide 60 g + Regular Insulin
300
250
200
150
100
0
60
120
180
240
Time Relative to Meal and Pramlintide (min)
Evaluable; Mean (SE); Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18;
Weyer C, et al. Diabetes Care 2003; 26:3074-3079; Pramlintide Acetate Prescribing Information, 2005
Symlin® Clinical Effects
Type 1 Diabetes Combined Pivotals
 A1C (%)
 Insulin Use (%)
0.0
-0.2
Placebo
Pramlintide
 Weight (kg)
10
1.0
5
0.5
0.0
-0.4
0
-0.6
-5
-0.8
2 4
8
13
Weeks
20
26
-10
-0.5
-1.0
ShortActing
LongActing
-1.5
2 4
8
13
Weeks
20
26
 No Symlin dose titration during initiation (fixed dose)
 No insulin dose reduction at Symlin initiation
Does Symlin® Work in Insulin Pump-Treated
Patients in a “Real-Life” Clinical Practice Study?
A1C
7-Point Glucose
0.0
 A1C (%)
-0.1
**
-0.2
-0.3%
-0.3
Blood Glucose (mg/dL)
195
-0.4
Baseline
Month 6
185
175
165
155
145
**
135
125
0
1
2
3
4
5
6
Breakfast
Month
Bedtime
-1
-2
†
-3
-3.2 kg
(-3.8%)
 Mealtime Insulin Use (%)
0
-4
-10
-20
†
-27.5%
-30
-40
0
1
2
3
Month
4
5
6
0
1
2
3
Month
<0.01; †P <0.0001 for changes from baseline; Hermann K, et al. Presented at
ADA, 71st Scientific Sessions; 2011; San Diego, CA (1065-P)
** P
Dinner
Mealtime Insulin
Body Weight
0
 Body Weight (kg)
Lunch
4
5
6
My Thinking About Symlin® Therapy
 Amylin is co-secreted with insulin
 We currently administer Symlin® as a
prandial hormone only
 What would happen if pramlintide was
administered in a “basal-bolus” fashion?
Continuous Subcutaneous
Pramlintide Infusion =
CSPI
CSPI: Proof of Concept
 13 type 1 adolescent patients (age = 17 years,
BMI = 22 kg/m2, HbA1c = 7.4%)
 Cross-over study
 CSII with “dual-wave bolus” of insulin
 CSII + CSPI with “dual-wave bolus” of insulin
and pram
 Results: 20% reduction of insulin dose, 26%
reduction in postprandial glucose, reduction in
glucagon levels
JCEM 2009:94, 1608
CSPI: Proof of Concept
“Simultaneous continuous sc
pramlintide and insulin infusion has the
potential of improving glucose
concentration by way of physiological
replacement”
JCEM 2009:94, 1608
So Why Can’t We Infuse Symlin® in
an Insulin Pump?
THE GOOD NEWS
PRESS RELEASE
JDRF and Amylin Partner to Investigate Co-Formulating Two Hormones for
Treatment of Type 1 Diabetes
May 10, 2011
http://www.jdrf.org/index.cfm?page_id=115726
THERAPY #3
 Incretin hormones
 Hormones from the gut which are secreted
in response to oral but not intravenous
glucose
 Responsible for reducing blood glucose
spikes
 GLP-1 = Glucagon-like Peptide-1
GLP-1 Modes of Action in Man
Upon ingestion of food…
• Stimulates insulin secretion
• Suppresses glucagon secretion
GLP-1 is secreted
from the L-cells
in the jejunum
and ileum
This in turn…
• Slows gastric emptying
• Reduces food intake
Long term effects
demonstrated in animals…
• Increases beta-cell cell mass and
maintains beta-cell efficiency
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412
Drucker DJ. Mol Endocrinol 2003; 17:161-171
Why Would This Be Helpful In Type 1
Diabetes?
 Could GLP-1 analogues, with similar
mechanisms as amylin (other than insulin
secretion), help A1C in type 1 DM?
 Could GLP-1 analogues improve beta cell
function in newly diagnosed type 1 DM?
 As of today, we have two GLP-1 analogues
 Byetta, injected twice daily
 Victoza, injected once daily
 (Bydureon, awaiting FDA approval)
Byetta and Type 1 DM
 Minimal literature
 My guess: tried “off label”
 Beta cell preservation
 One trial-didn’t help
Victoza and Type 1 DM
 Immediate reports of improvements in A1C
and weight.
 THIS is what we are all seeing around the
world with Victoza
OBERVATIONAL STUDY: Minimal scientific rigor
Eur J Endocrinol 2011;165:77-84
What About A “Controlled Study”?
“Honeymoon+Victoza”
70-180
70-180
< 70
70-180
No Victoza
70-180
> 180
No c-peptide+Victoza
70-180
70-180
Diabetes Care 2011;34:1463-1468
 Randomized to + or – Victoza
 A1c reduced in both groups
getting Victoza (6.6 to 6.4%
and 7.5 to 7.0%). No change
in non-Victoza group
 2 of the 10 patients still
making insulin could STOP
their insulin on Victoza
GLP-1: Where I Think This Is Going
 A 41-year-old woman, 25 years with type 1
diabetes, BMI 36 kg/m2, A1C 7.9% on insulin
pump therapy emails me about Victoza…
 “Yo Doc, just an ‘Oh, wow!’ moment for you.
Started the 1.2 dose. Had cereal for dinner.
Way bad, I know. Normally, I would have gone
over 200 for a few hours no matter how much
insulin I bolused. I never went over 130.
Never. Insurance covers it. Have a super-deeduper weekend.”
Case Study: A 36-Year-Old
with Type 1 Diabetes
 Type 1 diabetes for 1.5 years
 Started on metformin by the primary care
provider, then put on liraglutide (Victoza) in
April 2010 with an A1C of 6.6%
 Presents to me in September 2010
A1C = 5.2%
My Thoughts…
 The longer GLP-1 agonists may do better with type 1 DM
than the shorter-acting drugs
 More impact on both fasting and postprandial glucose
 Better tolerated than Symlin
 Most exciting is early data on beta-cell preservation
 Recall: obesity is a new problem for type 1 DM too-not so
20+ years ago
 What is needed: large clinical trials
 In the meantime: don’t expect insurance coverage in
Western Washington (poor coverage in type 2 diabetes!)
What about blocking
the enzyme that
breaks down GLP-1?
GLP-1 Secretion and Inactivation
Mixed
meal
Intestinal
GLP-1
release
t½ = 1 to 2 min
GLP-1 (7-36)
active
DPP-4
GLP-1 (9-36)
inactive
(>80% of pool)
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
Inhibition of DPP-4 Increases Active GLP-1
Mixed
meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
DPP-4
DPP-4
inhibitor
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
GLP-1 (9-36)
inactive
Several DPP-4s Available for Type 2
Diabetes
 Sitagliptin = Januvia
 Saxagliptin = Onglyza
 Linagliptin = Tradjenta
What about a DPP-4
inhibitor for type 1 DM?
Therapy #4: Sitagliptin (Januvia)
 20 patients, 8-week study
 Small but significant improvements in blood
glucose
 A1C decreased by 0.3%
 Time between 80-140 mg/dL increased
 No change in weight
 Larger, longer studies required
Diabetic Medicine 2011:28:1176-81
Therapy #5: What About Bile-Acid
Sequestrants for the Treatment of Type 1 DM?
 Bile acid sequestrants have been available for
decades for the treatment of high cholesterol
(hypercholesterolemia)
 Cholestyramine (Questran); colestipol
(Colestid); colesevelam (Welchol)
 The newest of these drugs, Welchol, is also
approved to treat type 2 DM-it lower A1C on
average by 0.5%
 Mechanism not known
What about a bile-acid
sequestrant for type 1 DM?
Mean + (SEM) LDL in the Control and Colesevelam
Treated Groups: N=40 Type 1 DM
140.0
130.0
P=0.02
P=0.01
P=0.003
LDL-C mg/dL
120.0
110.0
100.0
90.0
80.0
128.8 108.0
128.6
95.7
128.0
97.7
125.4
98.3
70.0
Placebo
Baseline
4 Weeks
Colesevelam
Visit
8 Weeks
12 Weeks
≥ 10% drop in LDL in the Rx group @ 4, 8, and 12 Wks
Garg et al, Diabetes Obesity and Metabolism, 2011
What About A1C?
 After 12 weeks, no significant reduction in
A1C
 My take: study under-powered to show a
reduction as the effect is real but small
Garg et al, Diabetes Obesity and Metabolism, 2011
How Might Bile Acid Sequestrants
Lower Glucose?
GLP-1 mean (±SEM) AUC
3500
GLP-1 AUC (pg/ml x min)
3000
Placebo
Colesevelam
p=0.02
2500
2000
p=0.03
1500
p=0.01
p=0.01
1000
500
p=0.13
0
-500
-1000
0
60
120
180
240
Time (minutes)
Garg et al, Diabetes Obesity and Metabolism, 2011
Bile Acid Sequestrants: What I See
 With huge use of statins, we rarely use these
agents
 However, when statins not tolerated I see an
obvious reduction in A1C levels in most
patients
 My take: more studies in type 1 DM needed
 Reasonable alternative for over 40 year old
patients who require statins and can tolerate
the huge pills (or gritty powder)
Therapy #6
 Raise you hand if you know what prolactin is
 Raise your hand if you know what
bromocriptine is
Bromocriptine
 Prolactin is the hormone responsible for
lactation and bromocriptine lowers prolactin
levels
 What in the world does this have to do with
diabetes?
Bromocriptine and Diabetes
 Mechanism isn’t clear, but bromocriptine
(Cycloset) improves diabetes control in type
2 diabetes
 A1C is generally reduced by 0.5%
 So what?
 In the one 3000+ cardiovascular disease
trial, bromocriptine lowered event rate
Therapy #7: Case 1
 Case: 31 year-old man diagnosed with type 1
diabetes at the age of 3 months. Frequent
severe hypoglycemia for many years
 Which non-insulin therapy should be
considered?
Neonatal Diabetes
 One of several gene mutations impairing
normal insulin secretion
 Infants usually quite ill, often DKA, always
prior to 6 months of age, usually before 3
months of age
 Gene mutations can be tested at Children’s
Hospital
 No need for insulin-treated with sulfonylureas
Case 2
 21 year-old woman presents with type 1 DM
diagnosed at age 14. Two brothers, a sister,
and her mother and maternal aunt all were
diagnosed with diabetes at the same time.
 What should our patient be treated with?
Maturity Onset Diabetes of Youth
MODY
 Hepatic Nuclear Factor 1α MODY (MODY-3)
 Most common type of MODY (60%)
 Usually presents in adolescence or 20’s
 Most often confused with T1DM
 In first few years, can achieve good
control with sulfonylurea
Sulfonylureas
 Stimulate insulin secretion
 Used for the treated of type 2 DM since the
1950s
 Glyburide, glipizide, glmeperide the most
common ones used
My Main Message Today: Don’t OverReact to Your Child’s A1C
First, it’s an imperfect test
Average Glucose vs. A1C
A1C
AG mg/dL (95% CI)
5%
97 (76-120)
6%
126 (100-152)
7%
154 (123-185)
8%
183 (147-217)
9%
212 (170-249)
What this means is
someone with an A1C
of 8% could have a
lower mean glucose
than someone else with
an A1C of 7%!
10% 249 (192-282)
11% 269 (217-314)
12% 298 (240-347)
Diabetes Care
31:1473-1478, 2008
Risk for Sustained DR in Conventional
and Intensive Treatment: How the
Controversy Started
Risk for Sustained DR in Subgroups of the DCCT
11%
24
10%
9%
20
Mean HbA1c
Conventional
16
But in 2008 we were told this analysis
was a “statistical artifact”
12
8%
8
7%
4
0
0
1
24
2
3
4
5
6
Time During Study (Years)
7
8
9
20
Intensive
16
12
8
9%
4
8%
7%
0
0
1
2
3
4
5
6
7
8
Mean HbA1c
9
Time During Study (Years)
Adapted from Diabetes 44:968-983, 1995
Fast Forward: 2011
 1604 adolescents stratified over 4 time
periods
 DR assessed with fundus photography
DOES THIS LOOK
FAMILIAR?
Diabetes Care 2011;34:2368-73
DR, MDI/CSII, A1C in 4 Time Periods
DR for CSII vs MDI: OR = 0.52
(95% CI 0.26-1.06), p = 0.07
Diabetes Care 2011;34:2368-73
The Bottom Line
 A1C is important, but not as important as
many thought in the past
 A1C only explains 11% of progression of
diabetic retinopathy-few appreciate this fact
 More data continue to suggest HOW the A1C
got to be what it is may be important-not just
the number itself!
Conclusions
 There are many possible agents to be used in addition
to insulin for the treatment of type 1 diabetes
 These agents are rarely used in pediatrics (T1D
Exchange data)
 Exercise is the big exception!
 Mechanisms of these agents often are not clear, yet
much excitement about “beta-cell health” with GLP-1
agonists
 A1C is important, but perhaps “A1C quality” is
important too
Conclusion
 What goes through my mind with each
patient:
Make sure it is type 1 DM!
Thank You