INSULIN IN THE OBESE PATIENT JACQUELINE THOMPSON RN, MAS, CDE SYSTEM DIRECTOR, DIABETES SERVICE LINE SHARP HEALTHCARE

INSULIN IN THE OBESE PATIENT JACQUELINE THOMPSON RN, MAS, CDE SYSTEM DIRECTOR, DIABETES SERVICE LINE SHARP HEALTHCARE

OBJECTIVES DESCRIBE INSULIN, INCLUDING WHERE IT COMES FROM AND WHAT IT DOES STATE THAT DIFFERENT KINDS OF INSULIN PREPARATIONS DIFFER AS TO SOURCE, STRENGTH, AND DURATION OF ACTION STATE THE IMPORTANCE OF ACCURATE TIMING OF INSULIN ADMINISTRATION DESCRIBE TREATMENT OPTIONS AVAILABLE

WHO IS HERE TODAY? PLEASE RAISE YOUR HAND IF YOU ARE : 1. PHYSICIAN 2. NURSE PRACTITIONER 3. NURSE 4. PHYSICIAN ASSISTANT 5. PHARMACIST 6. DIABETES EDUCATOR 7. DIETITIAN 8. ADMINISTRATOR 9. OTHER 3

NATIONAL DIABETES STATISTICS REPORT, 2014 29.1 million people or 9.3% of the U.S. population have diabetes Diagnosed: 21 million Undiagnosed: 8.1 million Estimated diabetes costs in the U.S. (2012) Total (direct and indirect): $245 billion Direct medical costs: $176 billion (2.3 x higher than people without diabetes) Indirect (disability, work loss, premature death): $69 billion 4 http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf

Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010 (*BMI 30, or about 30 lbs. overweight for 5 4 person) 1990 2000 2010 No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

Diabetes Among U.S. Adults 1990, 2000, 2010 1990 2000 2010 2016 No Data < 4% 4% 7.9% 8% 11.9% 12% 15.9% 16%

Population (%) Population (%) INCREASE IN DIABETES PARALLELS THE INCREASE IN OBESITY IN THE UNITED STATES Obesity* Diabetes 45 36 111% increase 37.7 12 10 43% increase 9.3 27 18 17.9 8 6 4 6.5 9 2 0 1998 2014 0 1998 2014 *BMI 30 kg/m 2. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283; Flegal KM, et al. JAMA. 2016;315:2284-2291. 7

BURDEN OF DIABETES

PREVALENCE OF DIABETES IN HOSPITALS IS HIGH AND INCREASING Number of discharges with diabetes as firstlisted diagnosis: 635,000 Average length of stay: 4.6 days How many patients discharged from your hospital have diabetes? 9 http://www.cdc.gov/nchs/fastats/diabetes.htm. Accessed August 5, 2014

SHARP HEALTHCARE PERCENT OF ACUTE INPATIENT DIABETICS CY 2010 TO 2017

DEFINITION OF DIABETES Metabolic alteration in the way the body uses food for growth and energy Type 1: autoimmune process beta cell destruction, lack of insulin production Type 2: resistance to insulin aided transport of glucose into muscle and adipose tissue; overproduction of glucose by the liver GDM (gestational diabetes): glucose intolerance that develops during pregnancy

ROLE OF INSULIN ANABOLIC HORMONE FACILITATES STORAGE OF NUTRIENTS GLUCOSE GLYCOGEN IN LIVER AMINO ACIDS PROTEIN IN MUSCLES FATTY ACIDS TRIGLYCERIDES IN FAT PREVENTS HEPATIC BREAKDOWN OF GLYCOGEN (GLYCOGENOSIS)

INSULIN ACTS LIKE A KEY http://www.nationwidechildrens.org/what-is-diabetes

INSULIN DEFICIENCY http://www.nationwidechildrens.org/what-is-diabetes

WHAT HAPPENS WHEN INSULIN IS INSUFFICIENT? CELLULAR STARVATION CATABOLIC PROCESS RELEASE OF NUTRIENTS GLUCOSE GLYCOGEN IN THE LIVER AMINO ACIDS PROTEIN IN THE MUSCLES FATTY ACIDS TRIGLYCERIDES IN THE FAT

HISTORY OF INSULIN IN THE U.S. 1922 The introduction of insulin began with pancreatic extract, first used to treat humans in 1922 (bovine insulin) by Banting and Best, and different preparations became available over the following decades. 1982 Human insulin was developed in the laboratory in 1978 and approved for therapeutic use in 1982, as a U100 insulin. 1980 Concentrated insulin was introduced in 1980, and recent years have seen the production of many concentrated insulin preparations including U200 and U300. 1998 Insulin analogues were introduced in 1998, with the approval of insulin lispro (Eli Lilly and Company, Indianapolis, IN), followed in 2000 by insulin glargine, which was developed as a peak less insulin. Analogue insulin is available in two main forms, rapid acting and long acting, as well as premixed combinations.

UNDERSTANDING INSULIN SENSITIVITY AND DIABETES Diabetes is a disorder in the way the body uses glucose, a sugar that serves as fuel for the body. When blood glucose levels rise, the pancreas normally make the hormone insulin, which signals cells to take sugar from the blood. Fat cells store excess glucose in the form of lipids (fats). In the most common form of diabetes, type 2, cells lose their sensitivity to insulin.

INSULIN RESISTANCE REDUCTION IN BIOLOGICAL RESPONSE TO INSULIN ASSOCIATED WITH BOTH GENETICS AND LIFESTYLE LACK OF EXERCISE, HIGH CALORIC DIET AND STRESSFUL LIFESTYLE - OBESITY INCREASED RISK OF CARDIOVASCULAR DISEASE NOT LIMITED TO TYPE 2 DIABETES DIABESITY

INSULIN RESISTANCE As the diabetes population gets heavier, daily doses of more than 100 units are more common. An increasing number of patients have severe insulin resistance and require large doses of insulin. Managing patients with severe insulin resistance is challenging because it is difficult to achieve good glycemic control using conventional treatment approaches Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. Large total daily dose requirements of standard U-100 insulin can be painful to administer and the onset and duration of insulin activity can be altered with high-volume doses.

PHYSIOLOGIC INSULIN SECRETION: DESIGNING AN INSULIN REGIMEN Insulin (µu/ml) 50 25 0 Basal Insulin 150 Breakfast Lunch Dinner Glucose (mg/dl) 100 50 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 A.M. P.M. Basal Glucose Time of Day

Insulin MAINTAINING PHYSIOLOGIC INSULIN DELIVERY IN THE HOSPITAL: BASAL BOLUS Correctional insulin Mealtime insulin (bolus) Normal Secretory Pattern of Insulin Basal insulin Breakfast Lunch Dinner Bedtime

INSULIN OPTIONS FOR BASAL INSULIN (CONTROLLING BG IN FASTING STATE) ANALOGS DETEMIR GLARGINE HUMAN NPH HUMULIN R U-500 OPTIONS FOR NUTRITIONAL INSULIN (CONTROLLING BG WHEN THERE IS CALORIC INTAKE) ANALOGS ASPART GLULISINE LISPRO HUMAN REGULAR Analogs cost about $270 per 10 ml vial, while Regular Human insulins such as Novolin and Humulin run about $120 per 10 ml vial.

PHYSIOLOGIC MULTIPLE INJECTION REGIMENS THE BASAL-BOLUS INSULIN CONCEPT BASAL INSULIN CONTROLS GLUCOSE PRODUCTION BETWEEN MEALS AND OVERNIGHT NEAR-CONSTANT LEVELS USUALLY ~50% OF DAILY NEEDS BOLUS INSULIN (MEALTIME OR PRANDIAL) LIMITS HYPERGLYCEMIA AFTER MEALS IMMEDIATE RISE AND SHARP PEAK AT 1 HOUR POST MEAL 10% TO 20% OF TOTAL DAILY INSULIN REQUIREMENT AT EACH MEAL

INSULIN ACTIONS

SUBCUTANEOUS INSULIN ADMINISTRATION Scheduled Sliding Scale Insulin only uses this component Basal Nutritional Correctional Total daily insulin needs Longacting insulin Rapid-acting insulin Trence DL, et al. J Clin Endocrinol Metab. 2003;88:2430-7. Moghissi ES, et al. Endocr Pract. 2009;15:353-369. Moghissi ES. Curr Med Res Opin. 2010;26:589-598. Clement S, et al. Diabetes Care. 2004;27:553-591.

GLUCOCORTICOIDS AND GLYCEMIC CONTROL Administration of glucocorticoids Adversely affects carbohydrate metabolism Worsens glycemic control in patients with diabetes Disproportionately affects postprandial glycemia Low Wang CC, Draznin B. Hosp Pract (1995). 2013;41(2):45 53. 26

INSULIN SUBCUTANEOUS POWER PLANS INSULIN SENSITIVITY: SENSITIVE: LEAN, ELDERLY, MALNOURISHED, RENAL IMPAIRMENT, TOTAL DAILY DOSE (TDD) <20 UNITS/DAY AVERAGE: TDD 20-40 UNITS/DAY RESISTANT: OBESE, RECEIVING CORTICOSTEROIDS, EXPERIENCING SEVERE INFECTION, TDD > 40 UNITS/DAY ENHANCED: HIGH DOSE CORTICOSTEROIDS, BLOOD GLUCOSE TARGETS NOT MET BY THE RESISTANT SCALE

STRIKING THE RIGHT BALANCE Hyperglycemia Hypoglycemia

INSULIN INJECTION SITES BE SURE TO USE A DIFFERENT INJECTION SITE EACH TIME AND DO NOT OVERUSE ANY SITE. REACTIONS AT THE INJECTION SITE (LOCAL ALLERGIC REACTION) SUCH AS REDNESS, SWELLING, AND ITCHING CAN HAPPEN. DO NOT INJECT INSULIN INTO A SKIN AREA THAT IS RED, SWOLLEN, OR ITCHY.

REAL LIFE RESULTS OF INSULIN RESISTANCE INSULIN MORE INSULIN COMPLICATIONS COMPLICATIONS WITH HIGH DOSES OF INSULIN WEIGHT GAIN FLUID RETENTION INCREASED RISK OF HYPOGLYCEMIA EXPENSIVE MULTIPLE INJECTIONS DAILY ADHERENCE DIFFICULTIES PAIN LARGE VOLUME OF INJECTION UNPREDICTABLE ABSORPTION

NON INSULIN MEDICATIONS FOR TYPE 2 ~MORE APPLICABLE IN THE OBESE ALTERNATIVE TREATMENTS OF TYPE 2 DIABETES: Metformin GLP 1 TZD DPP4 GLP 1 TZD DPP4 GLP1 TZD s SGLT2 METFORMIN DECREASES GLUCOSE PRODUCTION BY THE LIVER. FIRST LINE MED FOR TYPE 2 GLP 1 GUT, LIVER, PANCREAS - INCREASES SATIETY LEVELS BY SLOWING DOWN GASTRIC EMPTYING, INCREASES INSULIN RELEASE WITH FOOD, SUPPRESSES GLUCAGON SGLT 2 DECREASES GLUCOSE REABSORPTION IN THE KIDNEY (LOWERS RENAL THRESHOLD) TZD MUSCLE INCREASES INSULIN SENSITIVITY TZD s DPP4 GUT, PROLONGS ACTION OF GUT HORMONES, INCREASES INSULIN SECRETION, DELAYS GASTRIC EMPTYING. GLP1

ARE WE CONFUSED YET

WHY ARE CONCENTRATED INSULINS NEEDED? INSULIN THERAPY PLAYS A CRITICAL ROLE IN THE TREATMENT OF TYPE 1 AND TYPE 2 DIABETES MELLITUS AND WE ARE LOOKING FOR THE PERFECT SUBSTITUTE TO ENDOGENOUS PHYSIOLOGIC INSULIN PRODUCTION.. DESIRE TO FIND A BASAL INSULIN WITH 24-HOUR COVERAGE WITH FLATTER AND LESS VARIABLE INSULIN EXPOSURE PROFILE DESIRE TO LIMIT OR ELIMINATE THE RISK OF HYPOGLYCEMIA PROVIDE CLINICALLY NECESSARY HIGH DOSES OF INSULIN IN LOW VOLUME INJECTIONS FOR INSULIN RESISTANT PATIENTS

CONCENTRATED INSULIN

PROS AND CONS OF CONCENTRATED BASAL INSULIN THERAPY GLYCEMIC CONTROL WITH DEGLUDEC U200 AND GLARGINE U300 IS SIMILAR TO INSULIN GLARGINE U100 AND NOCTURNAL HYPOGLYCEMIA IS REDUCED NEWER CONCENTRATED BASAL INSULINS MAY OFFER AN ADVANTAGE IN TERMS OF REDUCED INTRAINDIVIDUAL VARIABILITY REDUCES THE INJECTION BURDEN IN INDIVIDUALS REQUIRING HIGH-DOSE AND LARGE VOLUME INSULIN THERAPY.

INSULIN GLARGINE U300 (TOUJEO ) SERUM INSULIN AND GIR PROFILE 60% of Gla-100 Exposed within the 1 st 12 hours Favorable basal insulin action providing sustained glucose lowering effect without increasing the risk for hypoglycemia Duration of Action is >30 hrs, Does not cause weight gain (-0.8%) 3X Concentration of glargine u-100 insulin Cost : $300-$400 for 3 pens (450 units per 1.5mL) Comes in a 1.5ml pen, once opened is good for 42 days Automatically delivers correct dose in less volume No Conversion calculation or adjustments required

TRESIBA FLEXTOUCH U-200 PEN Favorable basal insulin action providing sustained glucose lowering effect without increasing the risk for hypoglycemia Duration of Action is 42hrs, Does not cause weight gain (-1.3%) 2X Concentration of u-100 insulin Cost : $500 for 3 pens (600units per 3mL) Comes in a 3ml pen, once opened is good for 8 weeks Automatically delivers correct dose in less volume No Conversion calculation or adjustments required

U-500 INSULIN U-500R INSULIN HAS BEEN THE ONLY CONCENTRATED INSULIN AVAILABLE FOR USE SINCE THE 1950S HUMULIN-R U500 HAS A SIMILAR ONSET BUT LONGER DURATION OF ACTION COMPARED WITH U100 REGULAR INSULIN HUMULIN R U-500 CONTAINS 500 UNITS OF INSULIN IN EACH MILLILITER (5 TIMES MORE CONCENTRATED THAN HUMULIN R U-100) THIS CONCENTRATED INSULIN IS ESPECIALLY USEFUL FOR THE TREATMENT OF INSULIN RESISTANT PATIENTS WHO REQUIRE DAILY DOSES OF MORE THAN 200 UNITS PER DAY EXTREME CAUTION MUST BE OBSERVED IN THE MEASUREMENT OF DOSAGE BECAUSE INADVERTENT OVERDOSE MAY RESULT IN SERIOUS ADVERSE REACTION OR LIFE-THREATENING HYPOGLYCEMIA TO REDUCE THE RISK OF DOSING ERRORS THE ACTUAL DOSE FIELD SHOULD REFLECT BOTH UNITS AND VOLUME (IE.150 UNITS, 0.3ML) IN THE MAR COMES IN 3ML PEN (GOOD FOR 28 DAYS WHEN OPENED) AND 20 ML VIAL GOOD FOR 40 DAYS DOES CAUSE WEIGHT GAIN +4.9KG COST 6 MLS OF 500/ML (3) HUMULIN R U-500 KWIKPEN $576.67 OR $1,481.05 FOR 20ML VIAL

COMPARISON OF U-100 ML SYRINGE WITH HUMULIN R U-100 AND HUMULIN R U-500 DOSE 39

SAFETY MEASURES REQUIRED WITH RU-500 Standardized CPOE, with alerts to Pharmacist and Diabetes Educator Pharmacy home dose verification of R U- 500 insulin on admission Caution: Patients home dose may need to be significantly reduced due to dietary restrictions in the hospital The only syringe approved for use with U-500 insulin Pharmacy dispenses pre filled Volumetric syringe to the unit Discuss discharge dose based on expected dietary intake in the home setting 40

INSULIN PUMP IS USEFUL FOR OBESE PATIENTS TO REDUCE THE TOTAL DAILY DOSE (TDD)

POST-ACTIVITY QUESTION #1 PLEASE MATCH THE INSULIN FORMULATION WITH THE PROPER BRAND NAME INSULIN: 1) Glargine U300 a) Tresiba 2) Degludec U200 b) Humulin R 3) Regular U500 c) Humalog U200 kwikpen 4) Insulin Lispro U200 d) Toujeo

POST-ACTIVITY QUESTION #2 WHAT ARE THE COMMON RESULT(S) WHEN INSULIN RESISTANT PATIENTS HAVE TO USE LARGE VOLUMES OF INSULIN? a) UNPREDICTABLE ABSORPTION b) INCREASE PAIN c) LESS DISCOMFORT AT SITE OF INJECTION d) INSULIN LEAKAGE FROM INJECTION SITE e) A, B AND D

POST-ACTIVITY QUESTION #3 WHAT IS A COMMON REASON FOR USING CONCENTRATED INSULIN FORMULATION? a) INSULIN ABSORPTION HAS BECOME UNPREDICTABLE b) REDUCTION IN DAILY INJECTIONS c) REDUCED VOLUME OF INJECTION d) ALL THE ABOVE

POST-ACTIVITY QUESTION #4 WHAT ARE SOME OF THE FACTORS THAT LEAD TO INSULIN RESISTANCE? a) OBESITY b) GENETICS, STRESS AND LIFESTYLE c) LACK OF EXERCISE d) REFINED CARBS e) ALL THE ABOVE

POST-ACTIVITY QUESTION #5 INSULIN RESISTANCE IS A CONDITION DEFINED BY? a) INCREASED LEVELS OF INSULIN b) IMPAIRED CELLULAR RESPONSE c) INABILITY TO FACILITATE ENTRY OF GLUCOSE INTO THE CELL d) ALL THE ABOVE