1. Non-Insulin Therapies for the Treatment of Type 1 Diabetes
Irl B. Hirsch, MD
University of Washington School of Medicine

2. 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

3. Yes, I’m Frustrated

4. But I WON’T Surrender to Science or Common Sense
Which brings me to Therapy #1

5. Therapy #1 What is it? 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?

6. Exercise!

7. 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?

8. 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?

9. But What If You Are Not A Mouse?
Exp Diabetes Res 2011: epub Sept 2011

10. 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”

11. 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 %), 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

12. OMG
That’s not supposed to happen!

13. 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!

14. 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

15. 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

16. 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)

17. Pramlintide Improves Postprandial Glucose
Type 1 Diabetes
100
150
200
250
300 60
120
180
240
Time Relative to Meal and Pramlintide (min)
Plasma Glucose (mg/dL)
Plasma Glucose
(mg/dL)
Lispro Insulin
Pramlintide 60 g + Lispro Insulin
Regular Insulin
Pramlintide 60 g + Regular Insulin
Evaluable; Mean (SE); Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18; Weyer C, et al. Diabetes Care 2003; 26: ; Pramlintide Acetate Prescribing Information, 2005

18. Symlin® Clinical Effects
Type 1 Diabetes Combined Pivotals
Type 1 Diabetes Combined Pivotals
Placebo
Pramlintide
Placebo
Pramlintide
 Insulin Use (%)
 A1C (%)
 Weight (kg)
Short-
Acting
Long-
No Symlin dose titration during initiation (fixed dose)
No insulin dose reduction at Symlin initiation

19. Does Symlin® Work in Insulin Pump-Treated Patients in a “Real-Life” Clinical Practice Study?
** P <0.01; †P < for changes from baseline; Hermann K, et al. Presented at ADA, 71st Scientific Sessions; 2011; San Diego, CA (1065-P)

20. 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

21. 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

22. 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

23. So Why Can’t We Infuse Symlin® in an Insulin Pump?
THE GOOD NEWS

24. PRESS RELEASE http://www.jdrf.org/index.cfm?page_id=115726
JDRF and Amylin Partner to Investigate Co-Formulating Two Hormones for Treatment of Type 1 Diabetes
May 10, 2011

25. 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

26. GLP-1 Modes of Action in Man
Upon ingestion of food…
Stimulates insulin secretion
Suppresses glucagon secretion
Slows gastric emptying
GLP-1 is secreted
from the L-cells
in the jejunum
and ileum
Reduces food intake
This in turn…
Long term effects demonstrated in animals…
Increases beta-cell cell mass and maintains beta-cell efficiency
Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:

27. 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)

28. Byetta and Type 1 DM Minimal literature My guess: tried “off label”
Beta cell preservation
One trial-didn’t help

29. 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

30. OBERVATIONAL STUDY: Minimal scientific rigor
Eur J Endocrinol 2011;165:77-84

31. What About A “Controlled Study”?
“Honeymoon+Victoza”
70-180
70-180
< 70
No Victoza
70-180
70-180
> 180
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
No c-peptide+Victoza
70-180
70-180
Diabetes Care 2011;34:

32. 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 s 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-dee-duper weekend.”

33. 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

34. A1C = 5.2%

35. 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!)

36. What about blocking the enzyme that breaks down GLP-1?

37. GLP-1 Secretion and Inactivation
Mixed meal
Intestinal
GLP-1
release
GLP-1 (9-36)
inactive
(>80% of pool)
DPP-4
t½ = 1 to 2 min
GLP-1 (7-36)
active
Adapted from Deacon CF, et al. Diabetes. 1995;44:

38. Inhibition of DPP-4 Increases Active GLP-1
Mixed meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
DPP-4
DPP-4 inhibitor
GLP-1 (9-36)
inactive
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

39. Several DPP-4s Available for Type 2 Diabetes
Sitagliptin = Januvia
Saxagliptin = Onglyza
Linagliptin = Tradjenta
What about a DPP-4 inhibitor for type 1 DM?

40. Therapy #4: Sitagliptin (Januvia)
20 patients, 8-week study
Small but significant improvements in blood glucose
A1C decreased by 0.3%
Time between mg/dL increased
No change in weight
Larger, longer studies required
Diabetic Medicine 2011:28:

41. 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?

42. 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
120.0
110.0
LDL-C mg/dL
100.0
90.0
80.0
128.8
108.0
128.6
95.7
128.0
97.7
125.4
98.3
70.0
Baseline
4 Weeks
8 Weeks
12 Weeks
Visit
Placebo
Colesevelam
≥ 10% drop in LDL in the Rx 4, 8, and 12 Wks
Garg et al, Diabetes Obesity and Metabolism, 2011

43. 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

44. How Might Bile Acid Sequestrants Lower Glucose?

45. Garg et al, Diabetes Obesity and Metabolism, 2011
GLP-1 mean (±SEM) AUC
3500
3000
Placebo
Colesevelam
p=0.02
2500
2000
p=0.03
p=0.01
GLP-1 AUC (pg/ml x min)
1500
p=0.01
1000
p=0.13
500
-500 60
120
180
240
Time (minutes)
-1000
Garg et al, Diabetes Obesity and Metabolism, 2011

46. 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)

47. Therapy #6 Raise you hand if you know what prolactin is
Raise your hand if you know what bromocriptine is

48. Bromocriptine
Prolactin is the hormone responsible for lactation and bromocriptine lowers prolactin levels
What in the world does this have to do with diabetes?

49. 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 cardiovascular disease trial, bromocriptine lowered event rate

50. 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?

51. 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

52. 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?

53. 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

54. Sulfonylureas Stimulate insulin secretion
Used for the treated of type 2 DM since the 1950s
Glyburide, glipizide, glmeperide the most common ones used

55. My Main Message Today: Don’t Over-React to Your Child’s A1C
First, it’s an imperfect test

56. Average Glucose vs. A1C A1C AG mg/dL (95% CI) 5% 97 (76-120)
5% (76-120)
6% 126 ( )
7% 154 ( )
8% 183 ( )
9% 212 ( )
10% 249 ( )
11% ( )
12% 298 ( )
What this means is someone with an A1C of 8% could have a lower mean glucose than someone else with an A1C of 7%!
Diabetes Care 31: , 2008

57. But in 2008 we were told this analysis was a “statistical artifact”
Risk for Sustained DR in Conventional and Intensive Treatment: How the Controversy Started
Risk for Sustained DR in Subgroups of the DCCT 24 20 16 12 8 4
11%
10% 9%
Mean HbA1c
Conventional
But in 2008 we were told this analysis was a “statistical artifact”
Rate Per Patient Year 8% 7%
Time During Study (Years)
Intensive
Rate Per Patient Year 9% 8% 7%
Time During Study (Years) 24 20 16 12 8 4
Mean HbA1c
Adapted from Diabetes 44: , 1995

58. DOES THIS LOOK FAMILIAR?
Fast Forward: 2011
1604 adolescents stratified over 4 time periods
DR assessed with fundus photography
DOES THIS LOOK FAMILIAR?
Diabetes Care 2011;34:

59. DR, MDI/CSII, A1C in 4 Time Periods
DR for CSII vs MDI: OR = 0.52 (95% CI ), p = 0.07
Diabetes Care 2011;34:

60. 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!

61. 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

62. Conclusion Make sure it is type 1 DM!
What goes through my mind with each patient:
Make sure it is type 1 DM!

63. Thank You