Options for Medication Therapy RANDY ELDE, PHARMD, CDE, BC-ADM

Transcription

1 Options for Medication Therapy RANDY ELDE, PHARMD, CDE, BC-ADM

2 Financial disclosures Certified Insulin Pump & CGM trainer for Medtronic No other disclosures

3 Medications: Place in therapy? Medical Nutrition Therapy & increased Physical Activity must come first!

4 20+ years ago: Two Classes of Therapies Insulins Regular, Lente, NPH, Ultralente Sulfonylureas Diabinase, Orinase, Dymelor

5 Oral Class Mechanism Advantages Disadvantages Cost Biguanides Sulfonylureas Meglitinides TZDs Activates AMPkinase (?other) Hepatic glucose production Closes K ATP channels Insulin secretion Closes K ATP channels Insulin secretion PPAR-g activator Insulin sensitivity Extensive experience No hypoglycemia Weight neutral? CVD Extensive experience Microvascular risk Postprandial glucose Dosing flexibility No hypoglycemia Durability TGs (pio) HDL-C? CVD events (pio) Table 1. Properties of anti-hyperglycemic agents Gastrointestinal Lactic acidosis (rare) B-12 deficiency Contraindications Hypoglycemia Weight Low durability? Blunts ischemic preconditioning Hypoglycemia Weight? Blunts ischemic preconditioning Dosing frequency Weight Edema/heart failure Bone fractures LDL-C (rosi)? MI (rosi) Low Low Mod. Low Diabetes Care 2015;38: ; Diabetologia 2015; /s

6 Oral Class Mechanism Advantages Disadvantages Cost a- Glucosidase inhibitors DPP-4 inhibitors Bile acid sequestrants Dopamine-2 agonists SGLT2 inhibitors Inhibits a- glucosidase Slows carbohydrate digestion / absorption Inhibits DPP-4 Increases incretin (GLP-1, GIP) levels Bind bile acids? Hepatic glucose production Activates DA receptor Alters hypothalamic control of metabolism insulin sensitivity Inhibits SGLT2 in proximal nephron Increases glucosuria No hypoglycemia Nonsystemic Postprandial glucose? CVD events No hypoglycemia Well tolerated No hypoglycemia LDL-C No hypoglycemia? CVD events Table 1. Properties of anti-hyperglycemic agents Weight No hypoglycemia BP Effective at all stages Gastrointestinal Dosing frequency Modest A1c Angioedema / urticaria? Pancreatitis? Heart failure Gastrointestinal Modest A1c Dosing frequency Modest A1c Dizziness, fatigue Nausea Rhinitis GU infections Polyuria Volume depletion Mod. High High High High Diabetes Care 2015;38: ; Diabetologia 2015; /s

7 Injectable Class Amylin mimetics GLP-1 receptor agonists Insulin Mechanism Advantages Disadvantages Cost Activates amylin receptor glucagon gastric emptying satiety Activates GLP-1 R Insulin, glucagon gastric emptying satiety Activates insulin receptor Myriad Weight Postprandial glucose Weight No hypoglycemia Postprandial glucose Some CV risk factors Universally effective Unlimited efficacy Microvascular risk Gastrointestinal Modest A1c Injectable Hypo if insulin dose not reduced Dosing frequency Training requirements Gastrointestinal? Pancreatitis Heart rate Medullary ca (rodents) Injectable Training requirements Hypoglycemia Weight gain? Mitogenicity Injectable Patient reluctance Training requirements High High Variable Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015; /s

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9 How do we decide the appropriate choice? Overall patient condition Age Coexisting diseases, conditions, or abnormalities Presence of contraindications to certain medications Patient lifestyle Insurance coverage (cost) Willingness and ability to use injected medications (GLP-1 agonists, exogenous insulin) Characteristics and precautions of potential medications

10 Choices (cont d) What s right for me? Effect on Hemoglobin A1c Effect on glucose variability (how high & how low do I go) Effect on fasting blood sugar Effect on blood sugar after eating

11 Choices (cont d) Underlying pathophysiology Severity of abnormalities Degree of insulin resistance vs. insulin deficiency Presence and severity of glucose toxicity

12 Multiple, Complex Pathophysiological Abnormalities in T2DM incretin effect gut carbohydrate delivery & absorption _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA _? + hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

13 Multiple, Complex Pathophysiological Abnormalities in T2DM GLP-1R agonists incretin effect DPP-4 inhibitors A G I s gut carbohydrate delivery & absorption Metformin hepatic glucose production _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA Bile acid sequestrants + Insulin Glinides S U s Amylin mimetics renal glucose excretion _ DA agonists T Z D s? peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

14 Medications that improve insulin action Biguanides metformin Thiazolidinediones pioglitazone (Actos)

15 Medications that increase insulin action Sulfonylureas glyburide, glipizide, glimepiride Meglitinides repaglinide (Prandin) D-phenylalanine derivatives nateglinide (Starlix)

16 Medications that restore or replicate incretin action, increase insulin secretion, & suppress glucagon secretion GLP-1 agonists (injected) exenatide (Byetta, Bydureon) liraglutide (Victoza) dulaglutide (Trulicity) albiglutide (Tanzeum) DPP-4 inhibitors sitagliptin (Januvia) saxagliptin (Onglyza) linagliptin (Tradjenta) alogliptin (Nesina)

17 Medications that slow glucose absorption α-glucosidase inhibitors acarbose miglitol

18 Medications that increase renal glucose excretion SGLT-2 inhibitors canagliflozin (Invokana) dapagliflozin (Farxiga) empagliflozin (Jardiance)

19 Medications of unknown action Bile acid sequestrants colesevelam (Welchol) Dopamine agonist bromocriptine (Cycloset)

20 Medications that provide additional insulin Exogenous pharmacologic insulin (injected) Rapid acting: aspart (Novolog), lispro (Humalog), glulisine (Apidra) Short acting: regular (Novolin R, Humulin R) Intermediate acting: NPH (Novolin N, Humulin N) Long acting: detemir (Levemir), glargine (Lantus) Exogenous pharmacologic insulin (inhaled) Rapid acting: insulin human inhalation powder (Afrezza)

21 What s coming soon? Insulin glargine U300 (300 units/ml) Currently available as 100 units/ml Concentrated version provides a flatter and more consistent level of insulin Insulin degludec More predictable and flatter level of insulin than previously available PEG-lispro insulin Again more consistent levels of insulin delivery

22 What s so good about insulin? Works faster Dosage can be controlled with greater accuracy Side effects are well known Relatively cost-effective Good A1c reduction Lipid profile improved Feel better, more energetic More flexibility in lifestyle not as bad as I thought More involved with care Prevent complications Better quality of life

23 Disadvantages of insulin compared to other therapies Fear of needles and pain with injections Weight gain Loss of flexibility in lifestyle and independence Fear of hypoglycemia View insulin as personal failure or sign of worsening disease Fear that insulin causes complications Fear they will lose support of family and friends

24 Administration of Insulin

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26 Figure 3. Approach to star ng & adjus ng insulin in T2DM Basal Insulin (usually with metformin +/- other non-insulin agent) Start: 10U/day or U/kg/day Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. For hypo: Determine & address cause; ê dose by 4 units or 10-20%. Diabetes Care 2015;38:140; Diabetologia 2015; / s

27 Figure 3. Approach to star ng & adjus ng insulin in T2DM Basal Insulin (usually with metformin +/- other non-insulin agent) Start: 10U/day or U/kg/day Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. For hypo: Determine & address cause; ê dose by 4 units or 10-20%. Add 1 rapid insulin* injections before largest meal If not controlled after FBG target is reached (or if dose > 0.5 U/kg/day), treat PPG excursions with meal-time insulin. (Consider initial GLP-1-RA trial.) Change to premixed insulin* twice daily Start: 4U, 0.1 U/kg, or 10% basal dose. If A1c<8%, consider ê basal by same amount. Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached. For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. Start: Divide current basal dose into 2/3 AM, 1/3 PM or 1/2 AM, 1/2 PM. Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached. For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. If not controlled, consider basalbolus. Add 2 rapid insulin* injections before meals ('basal-bolus ) Start: 4U, 0.1 U/kg, or 10% basal dose/meal. If A1c<8%, consider ê basal by same amount. Adjust: é dose by 1-2 U or 10-15% once-twice weekly to achieve SMBG target. For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. If not controlled, consider basalbolus. Diabetes Care 2015;38:140; Diabetologia 2015; / s

28 Figure 3. Approach to star ng & adjus ng insulin in T2DM # Injections 1 Basal Insulin (usually with metformin +/- other non-insulin agent) Start: 10U/day or U/kg/day Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. For hypo: Determine & address cause; ê dose by 4 units or 10-20%. Complexity low 2 Add 1 rapid insulin* injections before largest meal If not controlled after FBG target is reached (or if dose > 0.5 U/kg/day), treat PPG excursions with meal-time insulin. (Consider initial GLP-1-RA trial.) Change to premixed insulin* twice daily mod. Start: 4U, 0.1 U/kg, or 10% basal dose. If A1c<8%, consider ê basal by same amount. Start: Divide current basal dose into 2/3 AM, 1/3 PM or 1/2 AM, 1/2 PM. Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached. Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached. For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. 3+ If not controlled, consider basalbolus. Add 2 rapid insulin* injections before meals ('basal-bolus ) If not controlled, consider basalbolus. high Start: 4U, 0.1 U/kg, or 10% basal dose/meal. If A1c<8%, consider ê basal by same amount. Adjust: é dose by 1-2 U or 10-15% once-twice weekly to achieve SMBG target. For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. Diabetes Care 2015;38:140; Diabetologia 2015; / s Flexibility more flexible less flexible

29 Insulin action times background (basal) Insulin begins to work working hardest stops working effectively NPH (Humulin-N, Novolin-N) 2-4 hours 4-8 hours hours glargine (Lantus) 2 hours same all day hours detemir (Levemir) 1-2 hours relatively flat up to 24 hours depending on dose

30 Insulin action times mealtime (bolus) Insulin begins to work working hardest stops working effectively Rapid acting 5-15 minutes 1-2 hours 3-4 hours lispro (Humalog) aspart (Novolog) glulisine (Apidra) Short acting Regular minutes 2-3 hours 4-8 hours (Novolin-R, Humulin-R)

31 Insulin level ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulins Rapid (Lispro, Aspart, Glulisine) Short (Regular) Hours Long (Detemir) (Degludec) Long (Glargine) Hours after injection

32 VISUAL #1 All About Insulin Normal Blood Glucose and Insulin Levels 2004 American Diabetes Association 171

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36 How to dose insulin Type 1 diabetes Total daily dose (TDD) is typically units/kg; recommend starting with 0.5 units/kg Most common regimen is long-acting insulin (glargine or detemir) at once or twice a day plus rapid acting insulin (lispro, aspart, glulisine) at each meal Approximately 50/50 mix of long-acting (basal) to rapid-acting (bolus) At onset, often divide bolus dose in 3 equal parts until education on carb counting and correction dosing is taught Adjustments are then made based on both pre-meal BG checks and anticipated carb intake after calculating an appropriate insulin to carb ratio and an insulin correction factor for each patient

37 How to dose insulin Type 2 diabetes Basal insulin Starting dose of 10 units daily or weight based dose of 0.2 units/kg/day Titration Increase by 1 unit daily until FBG at target Increase by 2 units every other day until FBG at target Check FBG twice a week, calculate average, increase dose by 10% until FBG at target Bolus (mealtime) insulin Starting dose of 2-4 units before largest meal of the day Titration Increase by 1-2 units every 3-4 days to target or add another mealtime dose

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41 Hospital Glycemic Management Good glucose control yields improved patient outcomes Critical care data suggests that lowering glucose results in: Decreased mortality Decreased complications Decreased hospital stay Reasonable & achievable glucose targets in hospitalized patients ICU: mg/dl General med/surg ward: mg/dl (pre-meal); mg/dl (random)

42 Hospital Glycemic Management (cont d) Diabetes / Hyperglycemia very common Controversy over exact glycemic target distracts from larger issues Chaos and avoidable hyper- and hypo-glycemia are the rule Alternatives (SSI) don t work and can be dangerous Standardization / team approach / protocols / order sets / metrics

43 Key questions to consider in patient assessment What type of diabetes (Type 1, Type 2, new onset)? What is patient s outpatient diabetes regimen (insulin, oral agents)? What kind of control has patient had (HbA1c)? Blood glucose on admission? Nutritional status (NPO, normal diet)? Reason for admission, how long will patient be hospitalized?

44 Considerations with non-insulin options in the hospital Sulfonylureas are a major cause of prolonged hypoglycemia Metformin is contraindicated in patients with renal function, use of iodinated contrast dye, & any state associated with poor tissue perfusion (CHF, sepsis) Thiazolidinediones associated with edema and CHF α-glucosidase inhibitors are weak glucose lowering agents Amylin & GLP-1 agonists can cause nausea & exert greater effect on postprandial glucose Time action profiles of oral agents can result in delayed achievement of target ranges in hospitalized patients

45 Physiologic insulin replacement preferred Best control and flexibility Basal insulin controls glucose in between meals and suppresses hepatic glucose production Prandial insulin for post-prandial glucose spikes Correction insulin to correct pre-meal hyperglycemia

46 Sliding scale insulin Prolonged use as only treatment is strongly discouraged Sliding scale is reactive rather proactive Responds too late to poor BG control during preceding time interval Often results in a roller coaster effect on BG variability No track record of effectiveness, just tradition No insulin provided for premeal BG level within target range

47 Steering towards physiologic insulin replacement Standardized insulin order sets and protocols Critical care patients Non-critical care patients Transitions Peri-op situations

48 Why protocols? Consistency of care Development guidelines: Keep them simple Can t interrupt work-flow Design reliability into process Desired action is the default (not doing desired action requires opting out) Reminders & algorithms are built into order set e.g. incorporate HbA1c lab request into order set Integrate guidance on appropriate BG monitoring & insulin dosing into order set Make Sub-Q insulin regimens with scheduled basal insulin the default

49 Guidelines for frequency of monitoring Integrated into order sets and protocols For patients receiving IV insulin infusion: default should be every hour until stabilized, then every 2-3 hours For non-critical care patients: minimum for eating patient is before each meal & at bedtime; non-eating patient minimum is every 6 hours

50 Treatment of hypoglycemia All insulin order sets should refer to a hypoglycemia protocol For BG < 60: If patient can take PO, give 15gm of fast acting carbohydrate If patient cannot take PO, give 25 ml of D50 IV push Check finger BG every 15 minutes & repeat above if < 80

51 Inpatient Diabetes Resources AACE Inpatient Glycemic Control Resource Center Glycemic Control Resource Room cemiccontrol.cfm

52 Insulin Pump Therapy Delivers insulin automatically and continuously via a plastic or steel cannula Cannula is inserted by the pump user into subcutaneous tissue Cannula is changed every 2-3 days and is attached to an insulin-containing syringe housed in the pump that is driven by an electronic motor, controlled by pump s computer Insulin is administered as one or several basal rates plus boluses before meals Bolus dose is calculated based on expected carb intake plus a correction factor based on pre-meal BG Which insulin pump is right for you? See insulinpump.com

53 Insulin Pumps in the Hospital? ADA position statement Patients may continue use of CSII if they: Are mentally and physically able Understand sick day insulin adjusting Are on stable insulin doses Are well-versed in carbohydrate counting and have sufficient oral intake Important to consider excluding clinical factors applicable in hospital setting Presence of DKA/HHNS on presentation Critical illness mandating an ICU admission Mental incapacity and/or psychological/psychiatric illness prohibiting safe use