Diabetes Medications at the End of Life. Goals and Objectives. Diabetes. Type 2 Diabetes Mellitus. Types of Diabetes

Transcription

1 Diabetes Medications at the End of Life Paul J. Schmidt Jr., R.Ph., M.S. Clinical Supervisor HospiScript Services Goals and Objectives Describe the Current Impact of Diabetes Mellitus on the Health Care System Review Insulin Products and their Current Applications Review Oral Hypoglycemic Medications and their Current Applications Describe Effective Management of Diabetes at End of Life Diabetes Diabetes is the leading cause of end-stage renal disease, adult blindness, nontraumatic lower extremity amputation and impotence. Heart Disease and Stroke are 2 to 4 times more common in people who have diabetes. Types of Diabetes Type 1 absolute lack of Insulin 5-10% Type 2 relative lack of Insulin 90-95% also referred to Insulin Resistance Type 3 General category for DM induced chemically (steroid therapy) or by other means Gestational 4% of pregnancies at weeks and predisposes to DM Type 2 Type 2 Diabetes Mellitus 9 years to diagnose Type 2 DM 50-80% of beta cell functioning has been lost at time of diagnosis Microvascular disease is related to fasting blood sugars and starts at time of DX Macrovascular disease is related to postprandial blood sugars and starts 9 years before a DX

2 Diabetes in the United States 24 million with DM with > 7 million undiagnosed 23.8% of individuals over the age of 60 with DM (diagnosed or undiagnosed) 60 million have prediabetes Largest percent increase is in y/o age group Costs of Diabetes in the U.S. At least $215 billion annually > $145 billion in direct medical costs > $60 billion in reduced productivity Centers for Disease Control and Prevention Diabesity Over 2/3 of adult Americans are overweight (BMI > 25) and 1/3 are obese (BMI > 30) Lifetime risk of developing Diabetes for persons born in 2000 is 33% for men and 39% for women; for Hispanic women, it is 50% 5 th leading cause of death Why Should We Worry? World Wide every 10 seconds there is a diabetes related death World Wide every 10 seconds 2 people are diagnosed with Diabetes United States every 21 seconds a patient is diagnosed with Diabetes Ogden CL et al. JAMA. 2006; 295: Generations at Risk Teenagers are at increased risk of macrovascular events It is projected that parents will be outliving their children or carrying the extra burden of being the care takers Estimated age of death from diabetes for 1/3 of children born today is 50! Sugars and Disease Minimal fluctuations in blood sugars are linked to reduction in macrovascular disease Elevated Fasting blood sugars are linked to microvascular disease Elevated 2 hr post-prandial blood sugars are linked to macrovascular disease National Diabetes Information Clearinghouse

3 Five Organs Involved in Diabetes Pancreas Liver Peripheral tissue (muscle) G. I. Tract Brain Fat tissue may become the sixth broken organ Inzucchi SE. JAMA, 2002; 287: Signs and Symptoms of Hyperglycemia Poly s phagia, uria, dipsia Blurred vision Fatigue, weight loss Poor wound healing (cuts and scrapes) Dry mouth, dry itchy skin Impotence (male) Recurrent infections Hypoglycemia Blood Glucose < 50mg/dl Patients may or may not be symptomatic Blood Glucose < 40mg/dl Patients are symptomatic Blood Glucose < 20mg/dl Patients can have seizures or be comatose Signs and Symptoms of Hypoglycemia Mild tremor, palpitations, sweating and hunger, shakiness, nervousness Moderate headache, mood changes, irritability, decreased attention and drowsiness, fatigue, blurred vision, abdominal pain and nausea Severe unresponsiveness, unconsciousness or convulsions Nocturnal Hypoglycemia Tingling lips/tongue Headache Nightmares Diaphoresis Difficulty arising in the morning Results of DCCT 1993 Tight Control Group 76% Reduction in Retinopathies 50% Reduction in Nephropathies 60% Reduction in Neuropathies 35% Reduction in Total Cholesterol Study group ranged in age from 13 to 39 n = 1441 Avignon A et al. Diabetes Care. 1997; 20:

4 ABC Goals A A1C 7% B Blood Preprandial mg/dl Postprandial < 180 mg/dl B/P < 130/80 mmhg C Cholesterol LDL < 100 mg/dl Triglycerides < 150 mg/dl HDL > 40 mg/dl M and > 50 mg/dl F ADA 2008, ACE 2007 Hypoglycemic Reactions/DCCT Three times more common in patients treated with intensive insulin therapy Nocturnal hypoglycemia accounted for 41% total hypoglycemic episodes DCCT 1993 Hypoglycemia Treatment 10g carbohydrate: 1) OJ or regular soda 1/2 cup 2) Apple Juice 1/3 cup 3) Sugar 2 tsp or 2 cubes 4) Lifesavers 5-6 pieces 5) B/D Glucose tabs 2 tablets Glucagon Dose = 1mg SubQ or IM to deltoid or anterior thigh Patient < 5 y/o = 0.25 to 0.5mg Patient 5 10 y/o 0.5-1mg Instruct others on how to mix the kit Position patient face down to avoid aspiration from vomiting Antidiabetic Agents Insulins Sulfonylureas Biguanide Thiazolidinediones (TZD s) Alpha-Glucosidase Inhibitors Meglitindies (Secretagogues) Incretin Mimetics Amylin Analogue Insulins Rapid Acting Short Acting Intermediate Acting Long Acting Combination Products

5 Rapid-Acting Insulin lispro (Humalog ) Types of Insulin Onset (h) Peak (h) Duration (h) 3-4 Insulin Injection Sites Insulin aspart (NovoLog ) Insulin glulisine (Apidra ) Short-Acting Rates of Absorption Insulin regular (Humulin R, Novolin R) Intermediate-Acting Insulin NPH (isophane suspension) (Humulin N, Novolin N) Insulin detemir (Levemir ) Insulin zinc suspension (Lente ) Long-Acting Insulin glargine (Lantus ) Combinations Insulin aspart protamine suspension and insulin aspart (Novolog Mix 70/30) * Dual Site Absorption ½ life (min) Abdomen 87 + or 12 Arm or 23 Hip or 28 Thigh or 15 Insulin lispro protamine and insulin lispro (Humalog Mix 75/25 ) Dual Insulin NPH suspension and insulin regular solution (Novolin 70/30) 0.5 Dual *Insulin glargine has no pronounced peak. Insulin Factors Altering Clearance Renal Function Decreased renal function will decrease insulin clearance and prolong or intensify insulin activity Insulin Antibodies IgG antibodies bind insulin as it is absorbed and release it slowly, delaying or prolonging the effect. Thyroid function Hyperthyroidism increases clearance but also increases insulin activity making control more difficult. Patients do stabilize as they become euthyroid. Lantus Dosing A change is dose is not necessary from once daily NPH or Ultralente to once daily glargine (Lantus) A 20% decrease in total daily dosage is necessary when converting from twice daily NPH to once daily glargine Initial doses in the elderly should be conservative to avoid hypoglycemia Sulfonylureas First generation (chlorpropamide very long half life) really no longer used Second generation - Glyburide (Diabeta, Micronse) - Glipizide (Glucotrol, Glucotrol XL) Third generation - Glimepiride (Amaryl) Sulfonylureas MAO Increase insulin secretion by binding to the surface of pancreatic beta cells There may be some reduction in hepatic glucose output and peripheral resistance but this is less pronounced Hypoglycemia is primary side effect These are not glucose dependent and lower B/S regardless of baseline

6 Sulfonylureas Efficacy can drop blood sugars 60-70mg/dl Will drop blood sugar regardless of baseline Hgb A1c reduction % Hgb A1c marks long term (last days) due to glycosylation to red blood cells Sulfa Allergies Sulfonylureas Thiazide durietics Lasix Celebrex All carry warnings about sulfa sensitivities. Most people can take the other stuff if they have had a sensitivity reaction to one or another. Lasix can cause a rash but the literature dose not strongly support the idea of cross sensitivity. Biguanides Metformin is the only currently marketed biguanide in the U.S. Primarliy reduces hepatic glucose production but some activity on peripheral tissues (muscle and fat) Efficacy Reduction in FPG 50-70mg/dl Reduction in HgbA1c % Metformin Rate limiting side effects can cause G.I. distress, diarrhea, abdominal cramping. Dose should probably be started low and go slow. Lactic acidosis has always been discussed but not supported strongly in the literature. Favorable effects on body weight. Patients who have body weight problems are often started on metformin if possible and it may be the drug of choice for prediabetes patients who may be sedentary and can benefit from encouragement if they see body weight falling. Metformin MAO Decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization) Contraindications Lactic Acidosis Contraindicated in impaired renal function (M: SCr > 1.5mg/dl & F: SCr > 1.4mg/dl As patients lose muscle mass, SCr becomes less accurate as marker for true GFR. Calculating CrCl becomes more important and metformin should probably be held if SCr is anywhere higher than these numbers.

7 Thiazolidinediones (TZD s) MAO: Binds and activates a nuclear receptor (PPAR-y) which leads to an increase in glucose transporter expression. This dose not happen overnight and may take as long as 6 weeks to show effects. TZD s decrease insulin resistance by making the muscle and adipose tissue cells more sensitive to insulin. TZD s also suppress hepatic glucose production to some extent Often referred to as insulin sensitizers TZD s Decrease insulin resistance by making muscle and adipose cells more sensitive to insulin and suppressing hepatic glucose production Other effects Weight gain, edema Hypoglycemia (if taken with insulin or insulin stimulators) Contraindicated in patients with abnormal liver function or CHF Improve HDL cholesterol and triglycerides; usually LDL neutral TZD s Efficacy o Reduction in fasting plasma glucose (mg/dl) o Reduction in HgbA1c (%) o Efficacy can start to be achieved in 6 weeks, however, some patients may need up to 3-4 months or longer to see full effects, so not typically started in Hospice TZD s Other Effects o Weight gain, edema, and liver dysfunction o Contraindicated in patients with abnormal liver function or CHF (NYHA Class III & IV) o Liver function monitoring: Baseline, then periodically (Most are recommending checking at 3 to 6 months intervals) o Actos appears to have more favorable effects on the lipid panel TZD s Pioglitazone(Actos ) o 15, 30, 45 mg o Dosing Range 15-45mg/day Rosiglitazone (Avandia ) o 2, 4, 8 mg o Dosing Range 4-8mg/day (May dose 2 or 4mg bid) TZD s U.S. Boxed Warning]: Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure Edema not very responsive to diuretics

8 Beta Cell Preservation Glitazones (Thiazolidinediones or TZD s) Incretins Research shows these two groups may preserve or regenerate beta cell function Inzucchi SE. JAMA, 2002; 287: Alpha Glucosidase Inhibitors MOA: Block the enzyme that digest starches in the small intestine Efficacy o Reduction in fasting plasma glucose (mg/dl) oreduction in HgbA1c (%) Other Effects o G.I. (Nausea, Flatulence etc.) o Caution in liver disease and bowel disease Alpha-glucosidase inhibitors Acarbose (Precose ) o 25, 50, 100 mg o Dosing: 25 mg 3 times/day with the first bite of each main meal Miglitol (Glyset ) o 25, 50, 100 mg o Dosing: 25 mg 3 times/day with the first bite of each main meal Meglitinides MAO Stimulate insulin release through potassium channels bind in a glucose dependent fashion with short onset and duration of action Efficacy - Often used for postprandial spikes - Reduction in fasting blood glucose 65-75mg/dl - Reduction in Hgb A1c % Meglitinides Prandin (replaglinide) Dose 0.5 to 4mg P.O minutes before each meal, maximum dose 16mg daily Starlix (nateglinide) Dose 60 to 120mg P.O. 1 to 30 minutes before each meal Incretin Hormones Increase levels of GLP-1 in the body GLP-1 in the G.I. tract will signal the pancreas to shut down glucagon Exenatide Byetta analog of incretin and mimics incretin activity Sitagliptin Januvia inhibits DPP-IV enzyme resulting in prolonged incretin activity

9 Mechanisms of GLP-1-Based Treatment of Diabetes Stimulate glucose-dependent insulin secretion Decrease glucagon Slow gastric emptying Promote satiety and decrease body weight Improve beta-cell function How Do These Work? Activate GLP-1 Receptors Long-acting GLP-1 agonists/analogs (incretin/mimetics) - Exenatide (Byetta ) 5mcg and 10mcg Sub Q twice daily dosing - Liraglutide (Victoza ) 0.6mg Sub Q daily x 7 days then 1.2mg Sub Q daily x 7 days then 1.8mg Sub Q daily Byetta Byetta (exenatide) o Is approved for use in type 2 diabetics who have failed to achieve adequate glucose control with a sulfonylurea or metformin o First agent in a new drug class known as incretin mimetics. Byetta mimics the action of the hormone GLP-1, which enhances glucose-dependent insulin secretion, increases B-cell growth/replication, and slows gastric emptying. o Clinical trials indicate that Byetta may decrease HgbA1c by % when used in combination with oral hypoglycemics Amylin Co-secreted with Insulin and deficient in diabetes Within minutes of starting to eat, food is sensed in the G.I. tract Amylin then signals the brain that you are full This is especially deficient in Type 2 DM Symlin (pramlintide) Amylinomimetic co-secreted with insulin Prolongs gastric emptying Reduces postprandial glucagon secretion Reduces caloric intake through appetite suppression

10 o Symlin MOA: Symlin 1) Prolongation of gastric emptying time 2) Reduction of postprandial glucagon secretion 3) Reduction of caloric intake through centrally-mediated appetite suppression o Symlin may lower HgbA1c an average of 0.4% over six months Symlin Dosing Type 1 DM 15 Mcg SubQ AC titrate to a target dose of Mcg. Type 2 DM 60 Mcg SubQ AC titrate to 120 Mcg dose if no significant nausea Store similar to Insulin products Symlin and Byetta Both only available via subcutaneous injections and are usually given two to three times a day They both have high potential for hypoglycemia o Symlin with Insulin o Byetta with Sulfonylurea Dipeptidyl Peptidase IV (DPP-IV) Inhibitors Inhibit DPP-4 enzyme. Also know as the gliptins - Sitagliptin (Januvia ) 25mg, 50mg, and 100mg Once daily dosing - Saxagliptin (Onglyza ) 2.5mg, and 5mg Once daily dosing Blood Glucose Management In hospice patients, the goals change! No longer attempting to prevent longterm damage with regards to Microvascular Disease & Macrovascular Disease Attempting to make monitoring parameters more comfortable for the patient Pearls of Wisdom The uncommon presentation of common conditions is more common than the common presentation of uncommon conditions Many of the signs and symptoms of Hypoglycemia mimic many of our dying patient s other conditions

11 Renal Effects of Aging Decreased Glomerular Filtration Decreased Creatinine Clearance Decreased Renin Activity Decreased Urine Aldosterone leading to more Sodium and Water losses and increased risk of Dehydration Creatinine Clearance Rule of Thumb: 80 y/o patient with no documented history of renal insufficiency and has a serum creatinine = 1.0mg/dl then Creatinine Clearance is probably close to 40ml/min Creatinine clearance overestimnates GFR by 10-20% but is a reliable estimate. Changes at End of Life Patients eat and drink less Lower weight and less caloric intake can reduce insulin resistance and bring blood sugars down Lower weight can bring blood pressures down 5-10lb loss of body weight can reduce systolic B/P points Changes at End of Life Patients eat and drink less Lower weight and less caloric intake can reduce insulin resistance and bring blood sugars down Diabetes at End of Life Management of oral and injectable diabetic medications? Why is this important? o Remember S&S of Hypoglycemia. Risk vs. Benefit o In hospice patients, this often resembles agitation/restlessness/delirium o Most hospice patients have a declining appetite/decreased oral intake which make them more susceptible Effects on Blood Sugar Hormones causing hyperglycemia: epinephrine, thyroid hormones, growth hormone and corticosteroids. Drugs causing hyperglycemia: phenytoin, NSAIDS, thiazide diuretics Drugs causing hypoglycemia: alcohol, lithium, ACE inhibitors, beta blockers Beta blockers mask symptoms of hypoglycemia

12 Stress Factors Infection Pancreatitis Trauma Hyperthyroidism May want to look at Thyroid supplements May take up to 6 weeks to show effect of dosage change Angina/MI Diabetes in Hospice What are the patient s goals? Diet should be liberalized to patient s preferences Blood glucose monitoring as appropriate Avoid hypoglycemia Avoid symptomatic hyperglycemia Diabetes and Hospice Goals More liberal glycemic control Much less relevance of HgA1C Acceptable (?) blood sugars? mg/dl? mg/dl? mg/dl? Mcoubrie. EurJCancerCare 2004;14: Poulson. JPainSymptomManage 1997;13(6): Quinn. JPainSymptomManage 2006;32(3): Case Study #1 Patient JS has a PMH of type 2 DM, HTN, and CHF NYHA IV Her HbA1c was 7.8% at her last office visit. She is seen today with increased swelling in her extremities. What medication changes could you suggest? Current Meds: HCTZ 25mg daily Rosiglitazone 4mg daily Atenolol 25mg daily Lisinopril 10mg daily Glipizide 10mg BID Mulitvitamin Calcium/Vit D a. Increase the HCTZ to decrease the edema b. Stop the rosiglitazone c. Decrease her glipizide to 5mg bid Case Study #2 Questions? KG 63 y/o COPD patient PPS 30% HX includes HTN, DM II, CKD, CAD Current Insulins Lantus 50 u S.Q. qhs Novolin 70/30 20 u S.Q. qam and 45 u S.Q. qpm Humalog sliding scale before meals