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

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THE PANCREAS THROUGHOUT HISTORY 1550 BCE-Papyrus describes polyuria and its treatment 4th century BCE-Ayur Veda of Susruta (India) described sugarcream urine which attracted ants. 7th century CE-Chinese physician Chen Chuan recorded sweet urine in diabetes 1869-Langerhans describes islets 1909-the name insuline is suggested by Jean de Meyer (Brussels) 1921-Banting and Best-report discovering Insulin used in 1922

BANTING-1891-1941 & BEST-1899-1978 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

Prevalence of Diabetes in the US Diagnosed Type 1 Diabetes 1.5 Million(1:400-600 children) Diagnosed Type 2 Diabetes 14 million Undiagnosed Diabetes 6 Million 1.5 million new cases of diabetes were diagnosed in people aged 20 years or older in 2005

Good Glycemic Control (Lower HbA1c) Reduces Incidence of Complications DCCT 9  7% 63% 54% 60% 41%* Kumamoto 9  7% 69% 70% – UKPDS 8  7% 17-21% 24-33% – 16%* HbA1c Retinopathy Nephropathy Neuropathy Macrovascular disease In 3 separate studies, good control of blood glucose as measured through HbA1c dramatically lowers the risk of developing comoplications in diabetes. The risk of retinopathy is decreased by 60% with a drop of HbA1c from 9 to 7. Nephropathy decrease by some 50% and neuropathy decreased by 60%. * not statistically significant DCCT Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117. UKPDS 33: Lancet. 1998;352:837-853.

HbA1c and Microvascular Complications Retinopathy 15 13 11 9 7 5 3 1 Nephropathy Relative Risk Neuropathy 7 8 9 10 11 12 HbA1c, % 10

Incidence of Diabetes- Related Complications (%) Every 1% HbA1c Increase Above Goal Elevates the Risk of Diabetic Complications +37% Incidence of Diabetes- Related Complications (%) +21% +14% +12% It has been shown that with every 1% increase in HbA1c above normal range, the risk of developing cardiovascular complications increases dramatically as well. Increase in Any Diabetes-Related Endpoint Increase in Risk of Myocardial Infarction (MI) Increase in Risk of Stroke Increase in Risk of Microvascular Complications Adapted from Stratton et al. BMJ. 2000;321:405-412.

Physiology of Insulin and blood glucose secretion Basal Insulin Breakfast Lunch Dinner Just a little background on physiologic secretion of insulin. Normally, insulin is secreted at a basal level with increases during meal time. The increase in insulin during meal time is both a psychological reaction to the anticipation of food and also physiological rise in blood glucose after eating. From this, we can see that one of the biggest disadvantage of traditional insulin therapy is that the insulin injections given in traditional therapy has no correlation to what the patient is doing physiologically. Blood glucose Basal blood glucose

Insulin Preparations Action Peak Action Onset of Duration of Action Peak Action Humalog/Novalog 5 to 15 min 1 to 2 hr 4 to 6 hr Human Regular 30 to 60 min 2 to 4 hr 6 to 10 hr Human NPH 1 to 2 hr 4 to 6 hr 10 to 16 hr Human Lente 1 to 2 hr 4 to 6 hr 10 to 16 hr Human Ultralente 2 to 4 hr Unpredictable <24 hr Lantus 30minutes none 24hr Patients with diabetes are traditionally treated with an long acting insulin and a short acting insulin. The total daily dose is given as 2/3 in the morning with 2/3 of which in long acting form and 1/3 in short acting form. 1/3 of the total daily dose is given at dinner where ½ is in the form of long acting insulin and the other ½ in short acting form. The intent is to provide coverage throughout the day. However, this method does not correlated with normal physiologic levels of insulin and it does not take into account how much the person really eats in a day. In addition, patients on this treatment are subjected to a rigid diet which makes compliance a problem. In addition, patients are subjected to 3-6 injections a day.

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 “Don’t Do This, Don’t Do That” Mauriac syndrome - chronic insulin deficiency - stunted growth, hepatomegaly

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. Adapted from Litton J et al; J Pediatr 2002;141:490-495.

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 “low’s” and no need for bedtime snack

WHEN WE STARTED TO DABBLE-THREE SHOTS A DAY Lispro Lispro Insulin Effect NPH NPH B L S HS B Meals

Twice Daily vs. Three Daily Injections Rationale: Avoid Dawn Phenomenon and Somogyi Effect 872 adolescents evaluated over a 3-year period. Either regimen: Increased insulin dose. Deterioration of metabolic control. Increase in BMI. Females faired worse than males. Adapted from Holl R et al; Eur J Pediatr. 2003 Jan; 162(1): 22-9.

New Long Acting Insulin (Glargine Insulin) Lantus is a new type of long acting insulin that has no peaks Mimics physiological insulin (basal) Newer long acting insulin such as lantus have no peak in blood stream thus mimics more physiological release of insulin.

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” Lispro Lispro Lispro Insulin Effect lANTUS B L S HS B Meals

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;141:490-495.

Better Control and Less Hypoglycemia in Young Children Purpose of Study: —        To determine if glycemic control could be achieved more effectively and safely using CSII Methods: —        9 toddlers with T1DM for a duration of > 6 months —        Mean age 34 months (range 20 – 58) —        Infusion sets were change every 2 days, most pts used a flexible set, several used a metal needle —        Duration of pump therapy: 12.7  1.6 months Results: —        HbA1c decreased from 9.5 to 7.9% (p < 0.001) —        Severe hypoglycemia decreased from 0.52 to 0.09 episodes per month (p < 0.05) —        HbA1c Hypoglycemia Frequency of parental contacts with health personnel declined by 80% from once every 5.9 to 46.3 days (p < 0.01) reflecting increasing parental confidence and independence in diabetes care —        All families preferred the pump to MDI and refused to consider a return to previous modes of insulin administration Conclusions: —        Our study demonstrates that pump therapy can reduce HbA1c and the frequency of moderate and severe hypoglycemia in poorly controlled preschool children —        Findings suggest that highly motivated and carefully supervised families can use the insulin pump to provide effective therapy for selected toddlers and preschool children with T1DM. HbA1c Hypoglycemia Litton J., J Pediatr 2002;141:490-495.

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

195 patients between the ages of 13 and 17 in DCCT: 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. 2001 Dec; 139(6): 804-12.

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. 2001 Dec; 139(6): 804-12.

“ 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.” Adapted from White, N et al, J Pediatr. 2001 Dec; 139(6): 804-12.

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. 2002 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

Purpose and Method of Study Purpose: compare two algorithms of management for newly diagnosed kids with diabetes in our clinic. Method: A study of HbA1c level and total daily insulin dose in 2 groups of patients with new onset diabetes type 1 at diagnosis, 6 months, and 12th months after diagnosis. The purpose of our study is to compare our newly diagnosed type 1 patients who are placed on pump therapy versus patients who were not placed on pump therapy in our clinic. To determine how well these 2 groups respond to our therapy, HbA1c level and total daily insulin dose in the 2 groups were examined at diagnosis, at 6 months, and at 12th month after diagnosis. Total number in study is 35, ages 15 month to 16 years. All patient were confirmed with GAD or islet cell antibodies to be afflicted with type 1 diabetes.

Hypothesis Our hypothesis are: Patients on pump have better control of their blood glucose level Better control allows extension of the “honey moon” period Our hypothesis are: Patients on pump have better control of their blood glucose level which is reflected in their HbA1c Better control allows extension of the “honey moon” period which is a period where the patient still has some insulin secretion from their pancreas. We hypothesize that this extension is the result of better control which lessen number of hyperglycemic insults to the pancreatic parenchyma thus allowing the beta cells to survive longer.

Treatment Algorithm Algorithm #1 Algorithm #2 Treatment algorithm Group 1 (number of patients = 24) Treatment algorithm Group 2 (number of patients = 11) All patients with new onset diabetes were discharged within 3-5 days. All patients with new onset diabetes were discharged within 24 hours. Patients and parents were taught within 3 to 5 days in-hospital how to manage diabetes by pediatric endocrinology team. Patients and parents were taught within first 24 hours in-hospital how to manage diabetes by pediatric endocrinology team. Patients were started on Humalog and NPH in the hospital after correction of diabetic ketoacidosis. Patients were started on Humalog and Lantus after correction of diabetic ketoacidosis and regiment was continued for the first 1-2 weeks. CSII was started within first 14 days after diagnosis. A pediatric endocrinologist was available 24 hours a day 7 days a week to support insulin dose adjustment and education over the phone for the patients and parents. This is a comparison of our treatment algorithm. Algorithm 1 is our old method. Patients in this algorithm stay in the hospital for 3-5 days. During this period patients are taught how to use NPH and insulin. Patient are reevaluated at 3mo, 6mo, and 1 year and have their HbA1c drawn at those periods. Algorithm 2 is our new pump method. Patients in this algorithm stay in the hospital for 24hours where the patient receive intensive teaching on how to use humalog and lantus. Pt are also taught on how to count carbohydrates and how to use the injection pens. Patients return to clinic at 2nd week to have their blood glucose followed up and at this time patient’s pump therapy is initiated. A pediatric endocrinologist was available 24 hours a day 7 days a week to support insulin dose adjustment and education over the phone for the patients and parents in both algorithms.

HbA1c This is a bar graph of our results. Y-axis is HbA1c and X-axis is time. From this you can see that HbA1c is significantly lower in individuals being treated on the pump (shown in dark purple) relative to individuals without a pump (shown in light blue) at the 12th month period. Interestly, there seems to be no difference in HbA1c level between the 2 groups at 6months.

Total daily dose This bar graph compares the amount of total daily dose between people on pump and patient who are not on pump. Y-axis represent units of insulin per kg per day. X-axis represent time. As you can see, people who are on the pump (shown in dark purple) uses a significantly smaller amount of insulin per day in comparison with patients who are not on the pump (shown in light blue).

Conclusion: Intensive teaching, 24 hour support, and CSII within 2 weeks of diagnosis improved patient’s HbA1c levels and decreased total daily dosage of insulin over traditional therapy. CSII was beneficial for newly diagnosed diabetes patients at the onset of disease. Thus, it is our conclusion that: Intensive teaching, 24 hour support, and CSII within 2 weeks of diagnosis improved patient’s HbA1c levels and decreased total daily dosage of insulin over traditional therapy. CSII was beneficial for newly diagnosed diabetes patients at the onset of disease.

Candidates for pump therapy 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 Typical Criteria Only motivated patients only patients who showed good compliance on previous regimen Adults and children > 6y old

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 HbA1c Age (yr) pre 3 mos post < 7 7.6 6.7 7-12 7.8 7.3 13-18 7.9 7.5 Ahern presented Yale’s experience with kids and pumps at the 2000 ISPAD meetings and noted improvements in HbA1c with no increase in hypoglycemia. The data from the youngest children was most significant. Children less than 7 years of age had the greatest improvement in HbA1c levels. Ahern et al., Journal of Pediatric Endocrinology and Metabolism 2000, 13(suppl 4):1220.

Additional Evidence From Yale Decreased hypoglycemia No change in BMI or TDD 98% remained on CSII Insulin Pump Therapy in Pediatrics: A Therapeutic Alternative to Safely Lower HbA1c Levels Across All Age Groups   Ahern JAH, Boland EA, Doane R, Ahern JJ, Rose P, Vincent M, Tamborlane WV Yale School of Medicine, New Haven, CT Background: While some of the initial pump patients of the 1970’s were pediatric patients, this therapy was initially used primarily with just adults. Over the last five years there has been increased interest in using pumps in children, however, some clinicians remain skeptical, despite many reports suggesting its usefulness in this population. Purpose of Study: The purpose of this paper was to describe the outcomes of a large group of children successfully using CSII at one center. Methods: Number of patients: Total: 161 with type 1 diabetes Preschoolers (1-6 yrs) 26 Schoolagers (7-11 yrs) 76 Adolescents (12-18) 59 Treatment: Pump therapy was offered to parents and patients who were performing  4 BG tests day, were motivated to achieve intensive treatment goals, or if the child had repeated episodes of hypoglycemia. A retrospective chart review was done on patients with at least 12 months on pump therapy. Results: Pump Use Average of 32 + 9 months (range 19-57) All children experienced a decreased in HbA1c (p <0.02, see figure). 98% patients (158 of the 161) remained on CSII. No significant change in BMI TDD pre vs post pump had no statistical change Preschoolers: 0.7 vs 0.8 u/kg Schoolagers: 1.0 vs 0.9 u/kg Adolescents: 1.3 vs 0.9 u/kg Severe hypoglycemia decreased (events/year) Preschoolers: 0.42 vs 0.19 Schoolagers: 0.33 vs 0.22 Adolescents: 0.33 vs 0.27 Total : 0.35 vs 0.24 (p <0.05) Conclusions: ·         Insulin pump therapy can result in an improvement in metabolic control with a simultaneous decrease in severe hypoglycemia in children of all ages with type 1 diabetes. ·         This improvement can occur without any deleterious effects on weight gain. ·         Insulin pump therapy should be offered and encouraged for children of all ages with type 1 diabetes to achieve the best outcomes. Ahern, JAH, et.al. Pediatric Diabetes 2002;3:10-15.

CSII vs. MDI With Glargine in Children 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) CSII (aspart) n=12 Randomized, Prospective Trial of CSII vs MDI with Glargine in Children: A Preliminary Report Elizabeth A. Boland, Stuart A. Weinzimer, Jo Ann H. Ahern, Amy T. Steffen, William V. Tamborlane Department of Pediatrics, School of Medicine, Yale University, New Haven, CT   Purpose: To compare CSII and MDI with glargine in youth with T1DM. Injection therapy MDI (aspart/glargine) n=14 Boland et al., Diabetes 2003, 52:S1, A45, 192-OR

Pump Group Achieved Better Control Overall Changes in HbA1c Levels 8.5 p=.30 (NS) p=.15 (NS) p=.001 p = .03 8 7.5 —        HbA1c was significantly lowered in the pump group and remained unchanged in the glargine-based MDI group (p = 0.03) —        7 Pump MDI 6.5 Baseline 4 wks 8 wks 12 wks 16 wks Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.

More Pump Wearers Achieved HbA1c 6.9% _ < % Patients Achieving HbA1c < 6.9% 10 20 30 40 50 The percent of patients able to achieve a HbA1c below 6.9% was higher in the pump treated group than the glargine-based MDI group (43% vs 12%). In addition: The pump group used 37% less insulin than the glargine-based MDI group (p < 0.05) The pump group had less hypoglycemia No DKA in either group Post study: all pumpers continued on pumps and 86% of MDIs switched to pumps —         Conclusion: —        Patients randomized to Glargine-based MDI therapy were able to achieve as good as control as they did on conventional injection regimens using the same total daily dose of insulin. —        Pump treated patients were able to significantly lower their HbA1c levels compared to both baseline values and the glargine group with a lower total daily dose of insulin. —       Insulin pump treatment is a more effective means to obtain strict metabolic control than glargine-based MDI therapy, in children with type 1 diabetes. Pump Glargine Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.

Sweden’s Experience 89 children 3-21 y.o Diabetes duration 6.1 years 30% using CSII HbA1c decreased from 9.2% to 8.4% after CSII start Severe hypos Pump: 11.1/100 pt years MDI: 40.3/100 pt years Sweden investigators presented their pediatric data at the 2000 ADA meeting and showed an improvement in HbA1c when pump therapy was used and much less severe hypoglycemia (approximately 25% of that experienced with MDI) . 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 - 0.025u 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):1142-1146.

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 Patients should leave insulin pens (or syringe and vial of fast-acting insulin) at home, in school, in parents’ handbag, at grandma’s or anywhere else they spend a lot of time

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