Diabetes Update Lanita S. Shaverd, Pharm.D. Director, UAMS 12 th Street Health and Wellness Center Assistant Professor, UAMS College of Pharmacy

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1 Objectives Review oral medications used for the treatment of diabetes Explain how to effectively combine oral diabetes medications for optimal results Discuss insulins and non-insulin injectable diabetes medications used for treatment Differentiate between action profiles of insulins and options for combining them in treatment Diabetes Update Lanita S. Shaverd, Pharm.D. Director, UAMS 12 th Street Health and Wellness Center Assistant Professor, UAMS College of Pharmacy Determine when it is appropriate to add insulin to an oral medication regimen Sharpen patient education counseling skills by practicing use of insulin syringes and bottles, insulin pens and other non-insulin injectables. Prevalence of Diabetes (2011) Estimated 25.8 million have diabetes Diagnosed 18.8 million people Undiagnosed 7.0 million 65 years and older 10.9 million (26.9%) have diabetes Background 20 years or younger 215,000 have diabetes (type 1 or type 2) 1.9 million 20 years or older newly diagnosed in Prevalence of Diabetes True prevalence of type 2 unknown Prevalence of Diabetes Diagnosis of type 2 increasing on children Leading cause of: Kidney failure Non traumatic lower limb amputation New cases of blindness 7 th leading cause of death 1

2 Complications of Diabetes Heart Disease and Stroke Hypertension Kidney Disease Blindness Nervous System Disease Amputations Dental Disease Complications of Pregnancy Other Complications Death Cost of Diabetes in the U.S. Direct medical costs 116 billion Indirect medical costs 58 billion Disability Work loss Premature mortality Total medical costs 174 billion Diabetes Prevention Glucose Control A1c < 7% Fasting: Post-prandial : < 180 Blood Pressure Control Goal BP < 140/80** mmhg ** Goal was increased from 130 to 140 in 2013 no reduction in mortality or non-fatal heart attacks Control of Lipids LDL <100 HDL > 40 Triglycerides < 150 Total Cholesterol < 200 Preventative Care Eyes Feet Kidneys Type 1 Diabetes 5-10% of all diagnosed diabetes cases Leading cause in children** Autoimmune disease Onset - acute Risk factors Autoimmune, Genetic, Environmental Co-morbidities Celiac disease, Autoimmune Thyroiditis Symptoms Polyuria Polydipsia Polyphagia Weight Loss Blurred Vision Fatigue Diabetic Ketoacidosis Type 2 Diabetes 90-95% of all diagnosed diabetes cases Usually starts as insulin resistance Becoming more frequent in children Risk Factors Overweight, Family History, Ethnicity, Age >10, Puberty Co-morbidities Hypertension, Lipid Disorders Type 2 Diabetes Associated with: Older age Obesity Family history History of gestational diabetes Impaired glucose metabolism Physical inactivity Race and ethnicity Symptoms Fatigue Polydipsia Nausea Polyuria Weight loss (in children) Frequent Infections/ Slow Wound Healing Blurred Vision 2

3 Gestational Diabetes Form of glucose intolerance More common among: AI, AA and H/L Americans Obese women Women with family history 5-10% of women diagnosed with type 2 after pregnancy 20-50% have chance of developing type 2 diabetes Pre-Diabetes Impaired Fasting Glucose (IFG) Fasting blood glucose: 100 to 125 Impaired Glucose Tolerance (IGT) Blood glucose after 2-hour oral glucose tolerance test Progression to diabetes not inevitable Weight loss and increase activity can delay or prevent progression Diagnosis of Type 1 Diabetes Onset of Symptoms Random Blood Glucose Fasting Blood Glucose Oral Glucose Tolerance Test (OGTT) Urine Glucose Urine Ketones Diagnosis of Type 2 Diabetes Physical Exam/Symptoms/History Fasting Blood Glucose Oral Glucose Tolerance Test (OGGT) Urine Glucose Urine Ketones Glycosylated Hemoglobin Glycosylated Hemoglobin Diagnosis of Type 2 in Children If age or weight fit one of these criteria: Age Older than 10 years At the onset of puberty or if occurs early Weight BMI > 85 th percentile for age and sex Weight > 120% of ideal for height Diagnosis of Type 2 in Children Plus any 2 of the following risk factors: Family history in 1 st or 2 nd degree relative Ethnic background of AI, AA, Asian or PI Signs of insulin resistance Presence of conditions associated with insulin resistance: Acanthosis nigricans Polycystic ovary syndrome (PCOS) Hypertension/Lipid disorders 3

4 Treatment of Diabetes Treatment Goals of Therapy Adults A1c < 7% Fasting: Post-prandial : < 180 Toddlers and preschoolers (0 6 years) A1c < 8.5 & >7.5 % Before meals: Bedtime/Overnight: School Age (6 12 years) A1c < 8 % Before meals: Bedtime/Overnight: Adolescents & Young Adults (13-19 years) A1c < 7.5 % Before meals: Bedtime/Overnight: Oral and Non-Insulin Anti-diabetics Medications Used for Treatment of Diabetes Biguanides 1 o decreases hepatic glucose output 2 o increases peripheral glucose uptake & use Sulfonylureas 1 o stimulates insulin secretion from pancreatic beta cells 2 o improves insulin sensitivity at the receptor and post-receptor levels; decrease hepatic glucose output Meglitinides stimulate rapid release of insulin from the pancreas with more rapid dissociation from the sulfonylurea receptor Medications Used for Treatment of Diabetes Thiazolidinediones promote glucose uptake into the skeletal muscle and adipose cells decrease insulin resistance increase insulin sensitivity Alpha-glucosidase Inhibitors competitively inhibitor the brush border alpha-glucosidases necessary for the breakdown of complex carbohydrates Dipeptidyl-peptidase-4 inhibitors (DPP4) Inhibits the dipeptidyl-peptidase-4 enzyme (DPP-4) responsible for the breakdown of incretin hormones glucagon-like pepetide-1 (GLP-1) and glucagon dependent insulinotropic polypeptide 4

5 Medications Used for Treatment of Diabetes Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor (New Class) Inhibits SGLT2 in the proximal renal tubule to reduce resorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose Amylinomimetics Modulates gastric emptying Decreases post prandial glucagon release Increases satiety Incretin Mimetics Stimulates the production of insulin in response to high blood glucose concentrations Inhibition of the release of glucagon after meals Slows the rate of gastric emptying Oral Anti-diabetics Biguanides Sulfonylureas metformin (Glucophage) metformin ER (Fortamet, Glucophage XR, Glumetza) mg once to twice daily mg once daily 1 2% No hypoglycemia in monotherapy Weight loss cardiovascular mortality in obese patients Adverse reactions: GI disturbances, anorexia on initiation Contraindications: SCr > 1.5 in men and Scr > 1.4 in women and CrCl < 60ml/min Drug Interactions: alcohol, iodinated contrast media, cimetidine glyburide (Micronase, DiaBeta) glyburide micronized (Glynase) glipizide (Glucotrol) glimepiride (Amaryl) mg twice daily mg twice daily mg twice daily 1 8mg once or twice daily 1 2 % Initiate lower doses in elderly Adverse reactions: hypoglycemia, GI disturbances, rash, photosensitivity, weight gain Contraindications/Warnings: decrease dose in hepatic impairment, Drug Interactions: other drugs that cause hypoglycemia glyburide not recommended in CrCl < 50ml/min Approved for use in children 1 2 % Same as above Adjust glipizide to 2.5mg in hepatic impairment 1-2 % Same as above Has an active metabolite Adjust glimiperide in CrCl < 20ml/min Meglitinides (Secretagogues) repaglinide (Prandin) nateglinide (Starlix) mg before meals (A1c < 8%: 0.5mg before meals; A1c > 8%: 1-2 mg before meals) 120mg three times daily before meals % Indicated for monotherapy or in combination metformin 15 minute onset, duration less than 4 hours Decreases postprandial blood glucose Adverse reactions: hypoglycemia, weight gain Drug Interactions: metabolize Adjust dose in CrCl < 40ml/min via CYP 3A4 More effective than nateglinide % Indication and onset same as above Decreased postprandial blood glucose Adverse reactions: hypoglycemia, weight gain Drug Interactions: metabolized via CYP 3A4 No dose adjustment in renal disease Less effective than repaglinide TZD s pioglitazone (Actos) rosiglitazone (Avandia) mg once daily 4-8mg once or in two divided doses % ( FBG by ) % ( FBG by ) Adverse Effects: hepatotoxicity do not start if ALT > 2.5x ULN or if AST increases > 2x ULN, edema, weight gain, fracture risk increased Contraindications: NYHA Class III/IV heart failure for initiation Drug Interactions: pioglitazone may decrease concentrations of oral estrogens Adverse Effects: hepatotoxicity do not start if ALT > 2.5x ULN or if AST increases > 2x ULN, edema, weight gain, fracture risk increased For rosiglitazone: possible increased risk of myocardial infarction new black box warning in November 2007 Contraindications: NYHA Class III/IV heart failure Drug Interactions: metabolized though CYP2C8 5

6 Alphaglucosidase Inhibitors acarbose (Precose) miglitol (Glyset) W1-2: 25mg at dinner, W3-4: 25mg at breakfast & dinner W5-12: 25mg with all 3 meals ( to 50mg TID if < 60kg and 100mg if >60kg) W1 25mg at dinner Titrate up to 25mg with all 3 meals, then may increase to 50mg with all meals in 4-8 weeks % (decreases postprandial blood sugars by ) % (decreases postprandial blood sugars by ) Usually not used a monotherapy Adverse Effects: abdominal pain, flatulence, diarrhea, increases LFT s, Contraindications: GI disorders Weight neutral Usually not used a monotherapy Adverse Effects: abdominal pain, flatulence, diarrhea, increases LFT s, Contraindications: GI disorders Weight neutral peptidase-4 inhibitors sitagliptin (Januvia) saxagliptin (Onglyza) linagliptin (Tradjenta) alogliptin (Nesina) 100mg daily (fasting by 16.2 and 2-hour postprandial by mg once daily % Indicated as monotherapy or in combination with metformin, pioglitazone or glimepiride Adverse Effects: hypoglycemia, severe allergic reactions (angioedema, skin reactions) Weight neutral Reduce dose when used in combination with secretagogues or insulin Dose adjustment in renal disease % Same as above CrCl <50ml/min 2.5mg 5mg once daily % Same as above No adjustment in renal disease 25mg once daily % Same as above Dose adjustment in renal disease down to 6.25mg daily Sodium- Glucose Cotransport Inhibitors canagliflozin (Invokana) 100mg daily (may increase to 300mg max dose) % Should be taken prior to first meal of the day Indicated as monotherapy or in combination Adverse Effects: increased potassium, renal insufficiency, hypoglycemia, genitourinary infections (females) Dose adjustment in renal disease and contraindicated in severe renal disease Commonly available oral combinations GlucoVance: glyburide & metformin Avandamet: rosiglitazone & metformin Metaglip: glipizide & metformin Actoplus Met: metformin & pioglitazone Avandaryl: rosiglitazone & glimepiride Janumet: sitagliptin & metformin Kombiglyze XR: saxagliptin & metformin Jentadueto: linagliptin & metformin Kazano: alogliptin & metformin Oseni: alogliptin & pioglitazone Incretin Mimetics Non insulin anti-diabetics exenatide (Byetta ) 5mcg twice daily within 60 min before breakfast and dinner x 30 days, then increase to 10mcg twice daily % in combination therapy Supplied as a subcutaneous injection pen Used as adjunct therapy for Type 2 diabetes not controlled with metformin, sulfonylurea or both. Adverse Effects: hypoglycemia, nausea, diarrhea, possible risk of pancreatitis, development of anti-exenatide antibodies Contraindications: cannot be substituted for insulin in Type 1, severe renal impairment, severe GI disease 6

7 Amylinomimetics pramlintide (Symlin) Type 1: 15mcg before major meals with titrations of 15mcg increments up to 60mcg Type 2: 60mcg before major meals, may increase to 120mcg in 3-7 days (nausea dependent) 0.5 % Supplied as an injection (5ml vials containing 0.6mg/ml) Approved for use in Type 1 and Type 2 (Type 1 = adjunctive therapy to mealtime insulin Type 2 = adjunct therapy to mealtime insulin with or without metformin and/or sulfonylurea) Decrease short/rapid acting insulin by 50% and monitor for hyperglycemia Adverse Effects: GI upset, nausea, anorexia Black box warning against insulininduced hypoglycemia, especially in Type 1 Drug Interactions: not for use with alpha-glucosidase inhibitors Contraindications: gastroparesis, hypoglycemia unawareness Insulins Type Onset Peak Effective Duration Type Onset Peak Effective Duration Rapid Actinq - lispro (Humalog) - glulisine (Apidra) - aspart (Novolog) min min min hours hours 1 3 hours 3 5 hours 3 4 hours 3 4 hours Insulin NPH/Insulin Regular - Humulin 50/50 - Humulin 70/30 - Novolin 70/30 30 min 30 min 30 min 2 5 hours 2 4 hours 2 12 hours hours hours Up to 24 hours Short Acting - regular (Novolin R / Humulin R) hour 2 3 hours 3 6 hours Intermediate Acting - neutral protamine hagedorn (NPH) (Novolin N / Humulin N 2 4 hours 6 10 hours hours Long Acting - glargine (Lantus) - detemir (Levemir) 4 5 hours 1 3 hours No peak Relatively flat 24 hours 20 hours Insulin lispro protamine/insulin lispro - Humalog 75/25 Mix - Humalog 50/50 Mix Insulin aspart protamine/insulin aspart - Novolog 70/30 Mix 15 min 15 min min hours hours hours hours 1-4 hours Up to 24 hours Insulin Dosing Guidelines Total daily dose of insulin based on total body weight Type 1: initial dose units/kg/day Type 1: with ketosis, during illness, adolescents in growth units/kg/day Type 2: Initial unit/kg/day Renal Insufficiency 0.4 units/kg/day Adjust doses using Fall Back method: fall back to most recent peak of the insulin and/or meal to identify where change is needed 4:00 8:00 12:00 16:00 24:00 4:00 Bolus Bolus Bolus Basal 7

8 REGULAR INSULIN INSULIN ASPART (NOVOLOG) NPH INSULIN 8

9 INSULIN GLARGINE (LANTUS) INSULIN DETEMIR (LEVEMIR) Severe Hypoglycemia: Glucagon Raises blood glucose level by stimulating the liver to release stored glucose Store at room temperature Expiration date: Monitor Hypoglycemic Emergency After mixing, dispose of any unused portion within one hour 9

10 Emergency Kit Contents: 1 mg of freeze-dried glucagon (Vial) 1 ml of water for reconstitution (Syringe) Severe Hypoglycemia Once mixed and drawn up, inject at 90 o angle into buttocks, thighs or arm May take minutes to regain consciousness Turn patient on side severe nausea Check blood sugar, give fruit juice or regular soda and advance diet as tolerated May experience hyperglycemia afterwards Combine immediately before use References Let s Practice Barnette, D. Endocrine and Metabolic Disorders. In: Barnette D, Bressler L, Brouse S, et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Course, Vol 2, 2008 ed. Lenexa, KS: American College of Clinical Pharmacy, 2008 pp Copeland K, et al. Type 2 Diabetes in Children and Adolescents: Risk Factors, Diagnosis and Treatment. Clinical Diabetes 2005; American Diabetes Association National Diabetes Education Program National Institutes of Health Thank You! Contact Information: Lanita Shaverd, Pharm.D. UAMS 4301 W. Markham Street, Slot 522 Little Rock, AR Office: Lswhite@uams.edu 10