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 GlucosePramlintide Improves Postprandial Glucose

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

100

150

200

250

300

0 60 120 180 240

Time Relative to Meal and Pramlintide (min)

Pla

sma

Glu

cose

(

mg

/dL

)

100

150

200

250

300

0 60 120 180 240

Pla

sma

Glu

cose

(mg

/dL

)Lispro Insulin

Pramlintide 60 g + Lispro Insulin

Regular InsulinPramlintide 60 g + Regular Insulin

Type 1 DiabetesType 1 Diabetes

No Symlin dose titration during initiation (fixed dose) No insulin dose reduction at Symlin initiation

Placebo Pramlintide

Type 1 Diabetes Combined PivotalsType 1 Diabetes Combined Pivotals

Symlin® Clinical EffectsSymlin® Clinical EffectsPlacebo

PramlintideType 1 Diabetes Combined PivotalsType 1 Diabetes Combined Pivotals

-0.8

-0.6

-0.4

-0.2

0.0

2 4 8 13 20 26Weeks

-10

-5

0

5

10

-1.5

-1.0

-0.5

0.0

0.5

1.0

2 4 8 13 20 26

Weeks

Insulin Use (%) A1C (%) Weight (kg)

Short-Acting

Long-Acting

** P <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)

0 1 2 3 4 5 6-0.4

-0.3

-0.2

-0.1

0.0

-0.3%

**

Month

A

1C

(%

)

0 1 2 3 4 5 6-4

-3

-2

-1

0

-3.2 kg(-3.8%)

†

Month

B

od

y W

eig

ht

(kg

)

0 1 2 3 4 5 6-40

-30

-20

-10

0

-27.5%

†

Month

M

eal

tim

e I

nsu

lin

Use (

%)

125

135

145

155

165

175

185

195Baseline

Month 6

Breakfast Lunch Dinner Bedtime

**

Blo

od

Glu

co

se (

mg

/dL

)

A1C 7-Point Glucose

Body Weight Mealtime Insulin

Does Symlin® Work in Insulin Pump-Treated Patients in a “Real-Life” Clinical Practice Study?

Does Symlin® Work in Insulin Pump-Treated Patients in a “Real-Life” Clinical Practice Study?

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?

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

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

JCEM 2009:94, 1608

“Simultaneous continuous sc pramlintide and insulin infusion has the

potential of improving glucose concentration by way of physiological

replacement”

So Why Can’t We Infuse Symlin® in an Insulin Pump?

THE GOOD NEWS

JDRF and Amylin Partner to Investigate Co-Formulating Two Hormones for Treatment of Type 1 Diabetes

May 10, 2011

PRESS RELEASE

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 GLP-1 Modes of Action in Man

GLP-1 is secretedfrom the L-cells

in the jejunumand ileum

GLP-1 is secretedfrom the L-cells

in the jejunumand ileum

This in turn…This in turn…

• Stimulates insulin secretion• Stimulates insulin secretion

• Suppresses glucagon secretion• Suppresses glucagon secretion

• Slows gastric emptying• Slows gastric emptying

Long term effectsdemonstrated in animals…Long term effectsdemonstrated in animals…

• Increases beta-cell cell mass and maintains beta-cell efficiency• Increases beta-cell cell mass and maintains beta-cell efficiency

• Reduces food intake• Reduces food intake

Upon ingestion of food…Upon ingestion of food…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker 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

Eur J Endocrinol 2011;165:77-84

OBERVATIONAL STUDY: Minimal scientific rigor

What About A “Controlled Study”?

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

“Honeymoon+Victoza”

No c-peptide+Victoza

70-180 70-180

70-180 70-180

70-180 70-180

No Victoza

> 180

< 70

Diabetes Care 2011;34:1463-1468

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-dee-duper weekend.”

Case Study: A 36-Year-Oldwith 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?

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 Secretion and Inactivation

IntestinalGLP-1

release

GLP-1 (7-36)active

Mixed meal

GLP-1 (9-36)inactive

(>80% of pool)

DPP-4

t½ = 1 to 2 min

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 (9-36)inactive

IntestinalGLP-1

release

Mixed meal

GLP-1 (7-36)active

DPP-4

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

DPP-4inhibitor

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

≥ 10% drop in LDL in the Rx group @ 4, 8, and 12 Wks

P=0.02 P=0.01 P=0.003

128.6 128.0 125.4108.0 95.7 97.7 98.3128.870.0

80.0

90.0

100.0

110.0

120.0

130.0

140.0

Baseline 4 Weeks 8 Weeks 12 Weeks

Visit

LD

L-C

mg

/dL

Placebo Colesevelam

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) AUCG

LP

-1 A

UC

(p

g/m

l x

min

)

-1000

-500

0

500

1000

1500

2000

2500

3000

3500

0 60 120 180 240

Time (minutes)

p=0.13

p=0.01p=0.03

p=0.01

p=0.02Placebo Colesevelam

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 YouthMODY

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 Over-React to Your Child’s A1C

First, it’s an imperfect test

5% 97 (76-120)

6% 126 (100-152)

7% 154 (123-185)

8% 183 (147-217)

9% 212 (170-249)

10% 249 (192-282)

11% 269 (217-314)

12% 298 (240-347)

Average Glucose vs. A1C A1C AG mg/dL (95% CI)

Diabetes Care 31:1473-1478, 2008

What this means is someone with an A1C

of 8% could have a lower mean glucose than someone else with an A1C of 7%!

0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9

24 24

20 20

16 16

12 12

8 8

4 4

00

Risk for Sustained DR in Conventional and Intensive

Treatment: How the Controversy Started

Conventional

Adapted from Diabetes 44:968-983, 1995

11%11%

Ra

t e P

er

Pa

tie

nt

Ye

ar

Ra

te P

er

Pa

tie

nt

Ye

ar 10%10%

9%9%

8%8%

7%7%

Time During Study (Years)Time During Study (Years)

Mean HbA1cMean HbA1c

Risk for Sustained DR in Subgroups of the DCCT

0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9

Intensive

Ra

t e P

er

Pa

tie

nt

Ye

ar

Ra

te P

er

Pa

tie

nt

Ye

ar

9%9%8%8%7%7%

Time During Study (Years)Time During Study (Years)

24 24

20 20

16 16

12 12

8 8

4 4

00

Mean HbA1cMean HbA1c

But in 2008 we were told this analysis was a “statistical artifact”

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

Diabetes Care 2011;34:2368-73

DR for CSII vs MDI: OR = 0.52 (95% CI 0.26-1.06), p = 0.07

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