Why We Pump Henry Anhalt, DO, CDE Director, Pediatric Endocrinology and Diabetes Saint Barnabas Medical Center Livingston, NJ

`In the past we had a light that flickered, in the present, a light that flames, and in the future we will have a light that shines over all the land and the sea Winston Churchill

Pump Gasoline?

Pump Iron?

Pump Breast Milk?

BANTING & BEST Orthopod who became a physiologist and died in air crash in Newfoundland while on wartime mission Together they isolated insulin and Banting won the Nobel Prize in 1923 knighted in 1934

First commercial insulin

Diagnosed Type 1 Diabetes 1.5 Million(1: children) Diagnosed Type 2 Diabetes 14 million Undiagnosed Diabetes 6 Million Prevalence of Diabetes in the US 1.5 million new cases of diabetes were diagnosed in people aged 20 years or older in 2005

DCCT Research Group. N Engl J Med. 1993;329: Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28: UKPDS 33: Lancet. 1998;352: HbA 1c Retinopathy Nephropathy Neuropathy Macrovascular disease DCCT 9 7% 63% 54% 60% 41%* Kumamoto 9 7% 69% 70% – UKPDS 8 7% 17-21% 24-33% – 16%* * not statistically significant Good Glycemic Control (Lower HbA 1c ) Reduces Incidence of Complications

HbA 1c and Microvascular Complications Relative Risk HbA 1c, % Neuropathy Nephropathy Retinopathy 10

Every 1% HbA 1c Increase Above Goal Elevates the Risk of Diabetic Complications Increase in Any Diabetes-Related Endpoint Increase in Risk of Myocardial Infarction (MI) Increase in Risk of Stroke Increase in Risk of Microvascular Complications Incidence of Diabetes- Related Complications (%) +21% +37% +12% +14% Adapted from Stratton et al. BMJ. 2000;321:

Physiology of Insulin and blood glucose Breakfast Lunch Dinner Basal Insulin Insulinsecretion Basal blood glucose Bloodglucose

Onset ofDuration of Action Peak Action Humalog/Novalog5 to 15 min1 to 2 hr4 to 6 hr Human Regular30 to 60 min2 to 4 hr6 to 10 hr Human NPH1 to 2 hr4 to 6 hr10 to 16 hr Human Lente1 to 2 hr4 to 6 hr10 to 16 hr Human Ultralente2 to 4 hrUnpredictable<24 hr Lantus30minutesnone 24hr Insulin Preparations

NPH and regular insulin - 2 injections Bkfst lunch dinner bedtime bkfst

Disadvantages of NPH/ Regular regimen No flexibility: Required certain amount of calories a day Skipped meal - hypoglycemia (peak of NPH) Exercise - hypoglycemia (excessive glucose use) At night - hypoglycemia (peak of NPH) Overeating- hyperglycemia (not enough) Oversleeping- hyperglycemia (skipped dose)

Results of conventional therapy Poor control - HbA1C 10% and higher Fear of hypoglycemia - worsening of control Inability to exercise - poor fitness Early development of complications OUT OF CONTROL-Negative reinforcement Dont Do This, Dont Do That Mauriac syndrome - chronic insulin deficiency - stunted growth, hepatomegaly

Adapted from Litton J et al; J Pediatr 2002;141: Some causes of hypoglycemia in toddlers and preschoolers: –Unpredictable food intake and physical activity. –Imprecise administration of low doses of insulin. –Frequent viral infections. –Inability to convey the symptoms of low blood sugar.

IN SEARCH OF THE HOLY GRAIL

Dr. Arnold Kadish of Los Angeles, California, devised the first insulin pump in the early 1960s. It was worn on the back and was roughly the size of a Marine backpack

Humalog/Novolog versus Regular Rapid acting insulins: Start in 10min Peak in 1-2h Gone in 3.5-4h Regular insulin: Starts in 30min Peaks in 3-4h Gone in 6-8h

Benefits of rapid acting insulins May be given just prior to the meal or after meal in babies Time of action match rise in sugar caused by most meals No action left at the time of next meal - no boluses buildups Less activity at bedtime - less night lows and no need for bedtime snack

New Long Acting Insulin (Glargine Insulin) Lantus is a new type of long acting insulin that has no peaks Mimics physiological insulin (basal)

INSULIN TACTICS The Basal/Bolus Insulin Concept Basal Insulin –Insulin requirement to suppress hepatic glucose production between meals Bolus Insulin (prandial) –Insulin requirement to maintain normal glucose disposal after eating –Insulin:CHO Ratio = 500/(total starting dose) –Correction Factor = 1500/(total starting dose) –Correction factor in young children = 1800/(total starting dose)

LANTUS AND NOVOLOG-POOR MANS PUMP BLSHSB Lispro Insulin Effect Meals Lispro lANTUS Lispro

Nine Preschool Patients Meticulously Cared For With MDI Switched To CSII: Mean A1c 9.5% reduced to 7.9%. –Severe hypoglycemic events 0.52 per month reduced to 0.09 per month. –Increased parental confidence and independence. –All refused to relinquish pump at completion of study. Adapted from Litton J et al; J Pediatr 2002;141:

Better Control and Less Hypoglycemia in Young Children Litton J., J Pediatr 2002;141: HbA1cHypoglycemia

Injections Also Fail To Achieve Glycemic Control Hypoglycemia: –MDI - 5 –CSII - 2 DKA: –MDI - 0 –CSII - 0 Preference –MDI - 4 of 16 –CSII - 14 of 16 Randomized, Prospective Trial of CSII vs. MDI with Glargine in Children HbA1c (%) Adapted from Doyle E Diabetes Care July 2004 Boland E et al; Diabetes 2003; 52 (Suppl. 1): 192

Adapted from White, N et al, J Pediatr Dec; 139(6): Glycemic Memory: Sustained Beneficial Effect Of Prior Intensive Therapy 195 patients between the ages of 13 and 17 in DCCT: –Decreased worsening of retinopathy by 74% (p < 0.001). –Decreased progression to proliferative or severe non-proliferative retinopathy by 78% (p < 0.007).

Adapted from White, N et al, J Pediatr Dec; 139(6): Glycemic Memory: Sustained Beneficial Effect Of Prior Intensive Therapy 195 patients between the ages of 13 and 17 in DCCT: –Relative risk of hypoglycemia < 1 among prior intensive group. –Prevalence of microalbuminuria 48% less. It is vital to achieve the best glycemic control early in the course in diabetes during adolescence and childhood.

Adapted from White, N et al, J Pediatr Dec; 139(6): Less than optimal glycemic control during the early years of diabetes has a lasting detrimental effect on the development and progression of complications, even after better glycemic control is established later in the course of the disease.

From Preschool to Prom 161 patients with type 1 diabetes: –26 ages 1 to 6 –76 ages 7 to 11 –59 ages 12 to 18 98% remained on CSII Reduced hypoglycemia (events/year) –Age 1 to 6: 0.42 to 0.19 –Age 7 to 11: 0.33 to 0.22 –Age 12 to 18: 0.33 to 0.27 Mean HbA1c levels Adapted from Ahern J et al; Pediatr Diabetes Mar;3(1): 10-5.

World youngest pumper in 1999: 5mo old

World youngest pumper 2003: 10 d old

I WAS A NON-BELEIVER TOO HARD/TIME CONSUMING I WAS UNINFORMED ON HOW TO USE THEM NOT FOR THE VERY YOUNG OR THE UNMOTIVATED ONLY AFTER HONEYMOON YOU HAVE TO TEST FOR ME TO PUT YOU ON PUMP YOU WILL SUFFER PSYCHOLOGICALLY

Introduction Test the feasibility and efficacy of insulin pump therapy initiated within the first month of diagnosis N=28 consecutive. mean age years Range of start 1-30 days None discontinued after up to three year follow- up 2 sites Cornell Medical Center and Maimonides Medical Center

Hypothesis Our hypothesis are: 1.Patients on pump have better control of their blood glucose level 2.Better control allows extension of the honey moon period

Rationale and Hypothesis Earlier aggressive glucose control leads to lower incidence of long-term complications Insulin pump therapy resembles physiology more closely than multiple daily injections Lower incidence of occult and overt serious and moderate hypoglycemia Would there be benefit to introducing pump therapy earlier rather than waiting until further insulinopenia sets in?

Demographics Range 26 months to 32 years Average time to pump start 16 days+ 11 days 3 went straight to pump and 2 started within one week

Mean HbA1c Levels Pre and Post Initiation

HbA1c

Insulin Burden (U/kg)

C Peptide AUC-In response to MMTT (Boost)

Other Significant Findings BMI-No significant gains or losses in BMI SD over study time All patients were self-sufficient within 3 months

Conclusions Starting patients on insulin pump therapy is a viable option at or soon after diagnosis Further studies need to be performed to see if quality of life and long term complications are affected Despite the labor intensivity of this approach the benefits were clear and patients opted to remain on pump therapy after treatment Apparent prolongation of the honeymoon

Candidates for pump therapy Typical Criteria Only motivated patients only patients who showed good compliance on previous regimen Adults and children > 6y old My Criteria Any patient who is willing to start and has abilities to learn May improve compliance Any age adults and children of any age (independent users 7-80 y old) Particularly non- compliant patients

ADVERSE EVENTS

PSYCHOSOCIAL OUTCOMES

The Yale Experience > 200 children started on pumps over last 5 yrs No difference in severe hypoglycemia Parents report less mild hypoglycemia Ahern et al., Journal of Pediatric Endocrinology and Metabolism 2000, 13(suppl 4):1220. HbA 1c Age (yr) pre3 mos post <

Additional Evidence From Yale Ahern, JAH, et.al. Pediatric Diabetes 2002;3: Decreased hypoglycemia No change in BMI or TDD 98% remained on CSII

CSII vs. MDI With Glargine in Children Boland et al., Diabetes 2003, 52:S1, A45, 192-OR CSII (aspart) n=12 MDI (aspart/glargine) n=14 Injection therapy Randomized, Parallel-group, 16 week study Subjects at baseline Age: 8-19 yr (mean 12.7 ± 2.7) Type 1 DM > 1 yr duration Standard insulin therapy (2-3 injections/day)

Pump Group Achieved Better Control Overall Changes in HbA1c Levels Baseline4 wks8 wks12 wks16 wks Pump MDI p =.03 p=.30 (NS) p=.15 (NS) p=.001 Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.

More Pump Wearers Achieved HbA1c 6.9% % Patients Achieving HbA1c < 6.9% Pump Glargine Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192. < _

Swedens Experience 89 children 3-21 y.o Diabetes duration 6.1 years 30% using CSII HbA 1c decreased from 9.2% to 8.4% after CSII start Severe hypos –Pump: 11.1/100 pt years –MDI: 40.3/100 pt years. Hanas, Diabetes, 2000, 49 (Suppl 1):A133.

Patient Characteristics of Successful Pediatric Pumpers Able to maintain follow up appointments with health care provider Willing to record blood glucose values Able to count carbohydrates Good family/social support system

Pump therapy benefits Improved control - more physiological basal rates (dawn phenomenon match), different boluses for food, less absorption variability Less hypoglycemia More flexible lifestyle and possibility to exercise Precise dosing - 0.1u u increments for basal rate and boluses Less injections - improved quality of life Less possibility of overdose Adapted from Plotnick L et al; Diabetes Care 2003; 26(4):

Pump Use in Children Is Increasing 200,000 users (adults and kids in the US). 10,000 are adults with type 2 diabetes ~ 20,000 children using pump therapy –10% of all children with diabetes Penetration as high as 90% in some pediatric clinics (ours) Increasing use in younger children (as young as 10 months) Current outcomes indicate CSII is safe and effective in children Increasing acceptance likely due to DCCT findings as well as the introduction of smaller, safer insulin pumps There are approximately 400,000 insulin pump users worldwide

Avoiding DKA Give a pen with the pump Instruct that any time the patient feels nauseated or has abdominal pain -- change the site Blood sugar is greater than 250 mg/dl –Take correction dose –Check for ketones –Recheck in 60 minutes If coming down, leave alone If not, take a shot and change the site

Summary Pump therapy is an intensive process for pediatric patients and their families and the diabetes education team. Successful pumpers are motivated and willing to maintain follow-up, carbohydrate count, and check blood glucose frequently. Benefits of pump therapy for pediatric patients include: improved lifestyle, decrease in hypoglycemia, accurate dosing, ability to review history to see if doses were actually given.

Summary Children with diabetes should be intensively treated to avoid short and long term complications Insulin pumps can provide better control and less hypoglycemia than MDI With good support and a standardized process, insulin pump therapy can help to improve diabetes management in children Insulin pump therapy should be the only form of therapy offered to children with diabetes

When meditating over a disease, I never think of finding a remedy for it, but rather, a means of preventing it. Louis Pasteur, 1884