Diabetes:What’s New?What’s Next?

Robert P. Hoffman, M.D.

Grand Rounds

June 1, 2007

Introduction

Frederick Allen 1919 “The knowledge of diabetes is advancing rapidly enough that even the patient whose outlook seems darkest should take courage to remain alive in the hope of a treatment that can be called curative”

1921 Banting and Best at the University of Toronto discovered insulin

DCCT

1993 1441 subjects (age 13-35) randomized to

intensive versus conventional therapy Intensive diabetes therapy markedly

reduces risk of long term complications in adults and adolescents

Increased risk of severe hypoglycemia Did not tell us how to achieve good

control

What’s New?, What’s Next?

New insulins New modes of delivery New tecnology Curative treatments Prevention

New Insulins

Insulin Structure

Zn

Short Acting Insulins

0 1 2 3 4 5Time Hours

Insu

lin

Glu

cose

Normal

Regular

Lispro AspartGlulysine

Long Acting Insulins

0 4 8 12 16 20 24Time Hours

NPH/Lente

INS

UL

IN

Glargine

Levomir

Glargine

Zn

pH =7.4

pH =4

Levomir

FFA

FFA

FFA

Intensive Insulin Regimens

Bf Lu Su Bt

Lispro Lispro Lispro

GlargineLevomir

Insulin Adjustment

Morn Lunch Supper Bed

LP LP GlaLP

Intensive Insulin Regimens

Lispro Lispro Lispro NPH

BF Lu Su Bt

Intensive Insulin Regimens

Lispro Lispro NPH

BF Lu Su Bt

NPH

Intensive Insulin Adjustment

Morn Lunch Supper Bed

LP NLP N

Advantages of New Insulins

Better post prandial glucose control Less nocturnal hypoglycemia Better schedule flexibility No major differences in overall glucose

control

Inhaled Insulin

Inhaled Insulin

Action profile similar to lispro Well tolerated by subjects Still need to take long acting Need to work out dosing

differences Small decrease in lung diffusion

capacity Long term safety unknown

New Technology

Continuous Glucose Monitoring

Maia and Arau´jo; Diab Res Clin Pract 2007,

Wilson et al, Diabetes care 2007

Change from baseline at 1 and 3 months of AIC. Values are means SE. P values correspond to the difference in change from baseline between the continuous and control groups. F, continuous group (arm 1); f, biweekly group (arm 2); OE, control group. Deis et al Diabetes Care 2006

Insulin Pumps

Continuous Subcutaneous Insulin Infusion (CSII)

Insulin Pumps

MiniMed

Infusion Sets

Results

Adolescents and Pumps

White et al Diabetes 2000

Randomized Adult

Tsui et al, Diabetes Care 2001

Randomized school age adolescents

Garcia-Garcia J Ped Endo Metab 2007– At 24 months randomized study MDI versus CSII

– Hemoglobin A1c was 7.70 +/- 0.64% vs 7.54 +/- 0.74% (p = 0.8);

– Body mass index SDS was 0.33 +/- 0.74 vs 0.40 +/- 1.01 (p = 0.9);

– Total daily insulin requirements were 0.95 +/- 0.10 vs 1.05 +/- 0.18 U/kg (p = 0.4),

– Incidence of severe hypoglycemia was 0.00 +/- 0.00 vs 0.04 +/- 0.14 episodes/patient/year (p = 0.8); and

– Incidence of ketoacidosis was 0.20 +/- 0.27 vs 0.04 +/- 0.14 episodes/patient/year (p = 0.2).

Preschool Children

Fox et al Diabetes Care 2007Wilson et al Diabetes Care 2005

Hypoglycemia

DKA-Metaanalysis

Eggar Diabetic Medicine 1997

Advantages to CSII

Effectively treats “dawn” phenomenon– Adjust basal rate at 3 AM

No shots Bolus for snacks without extra shot Flexibility of meals, exercise and travel

– Decreased need for snacks

Disadvantages to SCII

Requires more time/effort Contact sports, swimming, bathing can

be difficult Increased risk of DKA

Cure

Pancreas Transplant

Successful– 95% one year survival

– 70% one year insulin free

Problems– Life long immunosuppression

– Donor availability

Indications– Renal failure or near renal failure

– Combined pancreas kidney

Islet Transplantation

Results

Insulin free for 4 to 12 months– Normal hemoglobin A1c

– Near normal glucose profiles

– No complications

Problems– 2 cadaver pancreases per patient

– Harvesting technique critical

– Required immunosuppression

Autologous Bone Marrow Transplant

Complications

Prevention

Diabetes Prevention Trial Type 1– First degree relatives type 1 diabetic patients

» High Risk-received subcutaneous insulin No effect

» Intermediate Risk-oral insulin ongoing enrollment

No effect

European Nicotinamide Diabetes Intervention Trial

– No effect

TrialNet

Series of multicenter studies to prolong beta cell function or prevent type 1 diabetes

Prolong beta cell function– Anti CD3

– Anti CD20

– Anti CD3 plus GLP-1 agonist

Oral insulin

Conclusion

The knowledge of diabetes is advancing rapidly enough that all patients should work to maintain the best possible glycemic control to prevent complications now and in the future with the hope of new technologies and treatments that will make their task and lifestyle easier if not eliminate the disease all together.