Midwest Cardiovascular Research Foundation Welcomes DANITA HARRISON, ARNP Ms. Harrison discloses speaking relationships with Lilly, Novo Nordisk and Pfizer. Changing Diabetes: The time is now! Danita Harrison ARNP,CDE GHG Endocrinology 1
The problem Every 33 seconds someone dies from CAD ( one woman dies every 62 seconds) 21 million Americans have diabetes 1 in 3 Americans born in 2000 will have diabetes in their lifetime By 2025 300 million people worldwide may have T2DM 18% of people over the age of 65 have diabetes 2
Escalating Epidemic of Type 2 Diabetes Overweight rates are fueling the diabetes epidemic 1,2 References: 1. CDC Data and trends; 2. CDC Prevalence data. 3
High blood sugar & Obesity Having hyperglycemia produces many symptoms that that mirror the metabolic problems of having too much fat. ENDOTHELIAL DYSFUNTION OXIDATIVE STRESS VASCULAR INFLAMMATION ABNORMAL CLOTTING METABOLIC ABNORMALITIES HYPERTENSION ABNORMAL LIPIDS 4
Coronary Heart Disease Incidence by HbA1c Levels in Type 2 Diabetes Incidence (%) in 3.5 Years 25 20 15 10 5 0 Low < 6% CHD Mortality Middle 6% 7.9% HbA1c Tertile High > 7.9% Incidence (%) in 3.5 Years 25 20 15 10 5 0 All CHD Events Low < 6% Middle 6% 7.9% HbA1c Tertile High > 7.9% P < 0.01 vs lowest tertile; P < 0.05 vs lowest tertile. N = 1298 men and women. Patients 65 75 years old with or without type 2 diabetes at baseline. Reprinted with permission from Kuusisto J et al. Diabetes. 1994;43:960 967. 5
A1C Goals Unmet in Majority of Patients With Diabetes 10.0 12.4% have A1C >10% 1 9.5 A1C (%) 64.2% of patients with type 2 diabetes have A1C 7% 2 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 20.2% have A1C >9% 37.2% have A1C >8% ADA recommended target (<7%) 3 ACE recommended target (<6.5%) 4 Upper limit of normal range (6%) 1. Data from Saydah SH, et al. JAMA. 2004; 291:335-342 2. Calculated from Koro CE, et al. Diabetes Care. 2004; 27:17-20 3. Data from ADA. Diabetes Care. 2003; 26(suppl 1):S33-S50 4. Data from ACE. Endocrine Practice. 2002 Average Glucose A1C eag (mg/dl) A1c eag 5 97 8 183 5.5 111 8.5 197 6 126 9 212 6.5 140 9.5 226 7 154 10 240 7.5 169 10.5 255 6
Standard of Care Diet- refer to dietitian Exercise- daily Hypertension control Hyperlipidemia control Quit smoking ASA Home glucose monitoring Education- see a CDE! Traditional Treatment Options for Diabetes Increased Beta-Cell Workload (Insulin Resistance) Diminished Beta-Cell Response (Insulin (Insulin Deficiency) Deficiency) Biguanides: hepatic glucose output TZD: insulin sensitivity Alpha-glucosidase inhibitors: Slow the absorption of dietary starches SFU: insulin secretion Meglitinides: insulin secretion Insulin: Exogenous replacement Adapted from 2005 International Diabetes Center, Minneapolis, MN All rights reserved 7
Effects of Oral Therapies on A1c DRUG A1c % reduction Sulfonylureas 0.9-2.5 Biguanide (metformin) 1.1-3.0 a-glucosidase Inhibitors 0.6-1.3 DPP-4 inhibitors 0.8 Pramlintide 0.43-0.56 Exenatide 0.8-0.9 Thiazolidinedione 1.5 AACE Med Guidelines Clinic Practice for Management of Diabetes Mellitus 2007 8
Thiazolidinediones- Pioglitazone, Rosiglitiazone Should they be used? Warning: can cause or exacerbate CHF in some patients. Is not recommended in pt with symptomatic heart failure, or pt with established Class III or IV heart failure. Pioglitazone- Proactive A1c lower in pioglitazone group (6.9%) 5.3% lowering of LDL, 8.9% higher HDL, 13.2% lower triglycerides 10% lowering of the primary endpoint in the active group, not statistically significant. 16% reduction in secondary endpoints Heart failure and edema were increased 9
INCRETINS Gut hormones that enhance insulin secretion in response to food. Glucose dependent GLP-1 secreted from L cells of the intestine Incretin Effect 10
Byetta Exenatide (GLP-1 analogue) Injected bid Lowers fasting and pp bg, A1c level Slows gastric emptying, weight loss T2DM not controlled with oral hypoglycemics 11
Improvement in CV Risk Factors With 3.5 y of Exenatide Parameter Triglycerides (mg/dl) Baseline (Mean ± SD) 225±142 Δ Baseline (Mean ± SE) -44.4±12.1 95% CI -68.3 to - 20.5 Total cholesterol (mg/dl) 184±37-10.8±3.1-17.0 to -4.6 HDL-C (mg/dl) 39±10 8.5±0.6 7.2 to 9.7 LDL-C (mg/dl) 114±33-11.8±2.9-17.5 to -6.1 Systolic blood pressure (mmhg) 129±13-3.5±1.2-5.9 to -1.0 Diastolic blood pressure (mmhg) 79±8-3.3±0.8-4.9 to -1.7 3.5-y y completers, N = 151 Kendall D, et al. Diabetes. 2007:56(Suppl1):A149 Amylin Is Co-Secreted With Insulin 30 Meal Meal Meal Insulin Amylin Plasma Amylin (pm) 25 20 15 10 600 400 200 Plasma Insulin (pm) 5 7 am 12 noon 5 pm Midnight Time (24 h) 0 Healthy adults; n = 6 Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398 12
Amylin Is Deficient in Diabetes 20 Meal Plasma Amylin (pm) 15 10 5 Without Diabetes Late Stage Type 2 0-30 0 30 60 90 120 150 180 Time After Sustacal Meal (min) Type 1 Without diabetes; n = 27 Late-stage type 2; n = 12 Type 1; n = 190 Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398 Pramlinitide (Symlin) Synthetic amylin Injected before meals with insulin Lowers primarily pp bg Decreases A1c and weight Nausea is a side effect T1 and T2 DM not controlled with insulin 13
Pramlintide Clinical Effects TYPE 1 DIABETES COMBINED PIVOTALS Placebo + Insulin 30 or 60 μg Pramlintide TID or QID + Insulin Δ A1C (%) Δ Insulin Use (%) Δ Weight (kg) 0 Week 4 Week 13 Week 26 8 Week 4 Week 13 Week 26 1 Week 4 Week 13 Week 26-0.2-0.4-0.6-0.8 6 4 2 0-2 -4 0-1 -2 ITT; Mean (SE); P<0.05, P<0.01, P<0.0001; Placebo + insulin, N = 538, Baseline A1C = 9.0% ; Pramlintide + insulin, N = 716, Baseline A1C = 8.9% Pramlintide Acetate Prescribing Information, 2005; Data on file, Amylin Pharmaceuticals, Inc. Data from: Whitehouse FW, et al. Diabetes Care 2002; 25:724-730; Ratner R, et al. Diabetic Med 2004; 21:1204-1212 Pramlintide Clinical Effects TYPE 2 DIABETES COMBINED PIVOTALS Placebo + Insulin 120 μg Pramlintide BID + Insulin Δ A1C (%) Δ Insulin Use (%) Δ Weight (kg) 0 Week 4 Week 13 Week 26 8 Week 4 Week 13 Week 26 1 Week 4 Week 13 Week 26-0.2 6 4 0-0.4-0.6-0.8 2 0-2 -4-1 -2 ITT; Mean (SE); P<0.01, P<0.0001 Placebo + insulin, N = 284, Baseline A1C = 9.3%; Pramlintide + insulin, N = 292, Baseline A1C = 9.1% Pramlintide Acetate Prescribing Information, 2005. Data on file, Amylin Pharmaceuticals, Inc. Data from: Hollander P, et al. Diabetes Care 2003;26:784-790; Ratner RE, et al. Diabetes Technol Ther 2002; 4:51-61 14
S e c t i o n 12, 12.2 Mechanism of Action of Sitagliptin Glucose Ingestion of food Release of active incretins GI tract GLP-1 and GIP JANUVIA (DPP-4 inhibitor) Inactive GLP-1 X DPP-4 enzyme Inactive GIP Pancreas Beta cells Alpha cells dependent Insulin (GLP-1and GIP) Glucosedependent Glucagon (GLP-1) Glucose uptake by peripheral tissue Hepatic glucose production Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a meal. Blood glucose in fasting and postprandial states Concentrations of the active intact hormones are increased by JANUVIA (sitagliptin phosphate), thereby increasing and prolonging the actions of these hormones. S e c t i o n 14.1 Reduction of A1C : 2 Monotherapy Studies of JANUVIA at 18 Weeks Baseline A1C (%) Change in A1C, % 0.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1.6 Inclusion Criteria: 7% 10% Pooled Analysis Overall <8 8 <9 9 n=769 n=411 n=239 0.7 0.6 0.7 n=119 1.4-1.8 The magnitude of A1C lowering by strata varied by study. Reductions are placebo-subtracted. P<0.001 overall and for treatment by subgroup interactions. Combined number of patients on JANUVIA or placebo. Aschner et al. Diabetes 2006; 55:A462 15
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Using insulin would be ideal if it could imitate the natural process. MacLeod & Campbell 1925 Insulin Insulin may be anti inflammatory Insulin suppresses NFkB binding activity Reactive oxygen species ICAM PAI-1 Lipolysis and FFA formation 17
Plasm a insuli n levels Action Profiles of Injectable Insulin Analogues Aspart, glulisine, lispro 4 6 hours Regular 6 8 hours NPH 12 20 hours Ultralente 18 24 hours (No longer avail) Glargine 24 hours Detemir (6-24 hrs) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hours 18
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We have come a long way! A Revolution in Diabetes Management 20
Insulin pumps Who s an insulin pump candidate? 4 or more daily injections Blood glucose testing 4+ times daily Family and patient interested in pump & able to manage pump therapy Failure to achieve target A1C goal Frequent Hypoglycemia Erratic eating/lifestyle patterns Frequent DKA Blackett PR: Insulin Pump Treatment for Recurrent Ketoacidosis in Adolescence; Diabetes Care;1995;18:891-892 21
Continuous glucose sensor 68 y/o with HbA1c 8.5 % Tests twice a day: am and pm Never has had blood glucose above 123mg/dl 22
CareLink Download The patient is always the one in control. You may spend about 10-15 minutes with your patient face to face 4-5 x year Which leaves the patient in control 1435 minutes EVERY DAY! Teamwork is the ability to work together toward a common vision. It is the fuel that allows common people to attain uncommon results 23