7/6/ ANNUAL MEETING DIABETES - KEEPING UP WITH CHANGES TECHNICIAN OBJECTIVES PROJECTED PREVALENCE OF DIABETES IN THE UNITED STATES:

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1 TECHNICIAN OBJECTIVES Audience will be able to describe the differences between traditional and newer insulin products. DIABETES - KEEPING UP WITH CHANGES MARY HENCHER PHARMD, BCPS, CDE CLINICAL PHARMACIST, ENDOCRINOLOGY AND DIABETES NF/SG VETERANS AFFAIRS MEDICAL CENTER GAINESVILLE, FLORIDA Audience will be able to provide strategies on how technicians can be involved in medication reconciliation to improve patient outcomes. Audience will be able to list lifestyle changes that would be optimal f patients to follow who are transitioning from the inpatient to the outpatient setting. 4 CONFLICT OF INTEREST DISCLOSURES I have no conflicts of interest to disclose PROJECTED PREVALENCE OF DIABETES IN THE UNITED STATES: Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S21. 5 PHARMACIST OBJECTIVES Audience will be familiar with current diabetes care including newer treatment options and recent studies suppting these therapies, with a focus on type 2 diabetes. Audience will be able to describe the differences between traditional and newer insulin products. Audience will be able to identify strategies to help the patient transition from the inpatient to the outpatient setting with a good understanding of diabetes management. THE BURDEN OF DIABETES IN THE UNITED STATES The leading cause of: New blindness among adults Kidney failure Non traumatic lower limb amputations Increases the risk of heart attack and stroke by 2 4 fold Mtality rates 2 4 times greater than non diabetic people of the same age Diabetes also Doubles the risk of periodontal disease Doubles the risk of developing depression Increases patient s susceptibility to acute illness and wsens the prognosis (ex. pneumonia and influenza) 3 6 1

2 WHEN TO SCREEN FOR DIABETES Age 45 and older, particularly those who are overweight obese. Asymptomatic adults of any age with BMI 25 kg/m2 ( 23 kg/m2 in Asian Americans) who have 1 me additional risk facts. Repeat every 3-years if negative. Test overweight/obese children and adolescents with 2 me additional diabetes risk facts. METFORMIN - UPDATES April 2016: new recommendations from FDA with regards to use in kidney dysfunction: Check egfr befe starting metfmin and annually while patient is taking metfmin egfr below 30 ml/min/1.73m2: is contraindicated egfr ml/min/1.73m2: Starting metfmin is not recommended, but it may be continued if deemed appropriate after assessing the benefits and risks egfr >45ml/min: safe to use 7 10 DIAGNOSING DIABETES GLYCEMIC TARGETS HbA1c <7% (mean PG mg/dl) Pre prandial PG <130 mg/dl Post prandial PG <180 mg/dl Bedtime mg/dl Tighter targets ( %) younger, healthier Looser targets ( %) older, combidities, hypoglycemia prone, etc. *Or a random blood glucose reading of >200 mg/dl with symptoms of hyperglycemia 8 11 RISK FACTORS FOR PREDIABETES AND TYPE 2 DIABETES Age 45 years Family histy of T2D cardiovascular disease Overweight obese Sedentary lifestyle Non-Caucasian ancestry Previously identified IGT, IFG, and/ metabolic syndrome PCOS, acanthosis nigricans, NAFLD Hypertension (BP >140/90 mmhg) Dyslipidemia (HDL-C <35 mg/dl and/ triglycerides >250 mg/dl) Histy of gestational diabetes Delivery of baby weighing >4 kg (>9 lb) Antipsychotic therapy f schizophrenia severe bipolar disease Chronic glucocticoid exposure Sleep disders Obstructive sleep apnea Chronic sleep deprivation Night shift wk NON-INSULIN TREATMENT OPTIONS 9 2

3 PREFERRED OLDER VS NEWER TREATMENT OPTIONS DPP-4 INHIBITORS OLDER TREATMENT OPTIONS Biguanides Use in prediabetes if overweight/obese Sulfonylureas Sht duration of efficacy Thiazolidinediones Reduce free fatty acids; use in fatty liver disease, prediabetes studies ongoing NEWER TREATMENT OPTIONS Dipeptidyl peptidase-4 inhibits (DPP-4) Glucagon-like peptide-1 agonists (GLP-1) Sodium-glucose transpter-2 inhibits (SGLT-2) Sitagliptin*, Saxagliptin*, Linagliptin, Alogliptin* *Renal adjustments required Targets: post-prandial BG values; HbA1c lowering <1% Advantages: No hypoglycemia, well tolerated Disadvantages: possible immune-mediated dermatological effects (angioedema), possible acute pancreatitis, joint pain (FDA 8/2015), mixed evidence regarding heart failure risk Monotherapy Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Efficacy * Hypo risk Weight Side effects Costs Combination injectable therapy Healthy eating, weight control, increased physical activity & diabetes education low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 recept Insulin (basal) dione inhibit inhibit agonist intermediate intermediate est moderate risk low risk low risk low risk low risk risk gain gain neutral loss loss gain hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia low low variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea DPP-4-i SGLT2-i GLP-1-RA Insulin Thiazolidinedione SU DPP-4-i SGLT2-i GLP-1-RA Insulin Basal Insulin DPP-4 Inhibit SU SGLT2-i Insulin SGLT-2 Inhibit SU DPP-4-i Insulin GLP-1 recept agonist SU Insulin DPP-4-i SGLT2-i GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding SGL T2-i: Mealtime Insulin GLP-1-RA Insulin (basal) TECOS (TRIAL EVALUATING CARDIOVASCULAR OUTCOMES WITH SITAGLIPTIN) STUDY DESIGN N=14,671 patients with T2DM and CV disease Primary composite outcome: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization f unstable angina Secondary composite outcome: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. Median follow-up: 3 years KEY RESULTS Noninferi to placebo f cardiovascular outcomes Primary HR: 0.98 ( ); P<0.001 Secondary HR: 0.99 ( ); P<0.001 No difference between sitagliptin and placebo in incidence of infections, cancer, renal failure, hypoglycemia, noncardiovascular death DPP-4 INHIBITORS: MECHANISM OF ACTION Increases insulin secretion, decreases glucagon secretion DPP-4 INHIBITOR TRIALS - Updates DPP-4 inhibits are neutral with regard to CV effects FDA has revised labeling of saxagliptin and alogliptin to include a warning f patients with a histy of risk facts f heart failure (SAVOR-TIMI 53, EXAMINE trials) 2 observational studies have since shown DPP-4 inhibits are NOT me likely to cause hospitalizations f heart failure compared to other al agents; n increased risk of saxagliptin compared to sitagliptin Current trials evaluating DPP-4 vs sulfonylurea in patients with pre-existing cardiovascular disease Use with caution In your heart failure patients? 15 fda.gov 5/

4 GLP-1 AGONISTS SODIUM GLUCOSE COTRANSPORTER 2 INHIBITORS (SGLT2) 180 g/day/1.73 m 2 is filtered glucose load SGLT2 transpts 90% of filtered glucose out of tubular lumen SGLT1 transpts remaining 10% of filtered glucose SGLT1 is primary SGLT in small intestine 1image&view=detailv2&&id=B079D4566ADF732B732DACAFDF5F17AF0D6C6BE8&selectedIndex=0&ccid=E%2fW7ki2 j&simid= &thid=oip.m13f5bb922da35d34365f37dbda123261o0&ajaxhist= GLP-1 AGONISTS SODIUM GLUCOSE COTRANSPORTER 2 INHIBITORS (SGLT2) Twice daily: exenatide Once daily: liraglutide Once weekly: Exenatide long-acting, Albiglutide, Dulaglutide Glucose dependent increase in insulin secretion and decrease in glucagon secretion by activating GLP-1 recepts, also slows gastric emptying which increases satiety. Daily dosing targets post-prandial glucose; weekly dosing targets fasting glucose Advantages: No hypoglycemia, decreases appetite, promotes weight loss Contraindications: personal/family histy of medullary thyroid cancer, CrCl <30 ml/min (exenatide), gastroparesis Adverse effects Common: nausea, vomiting, diarrhea, injection site reactions, headache Rare: acute renal failure due to dehydration from gastrointestinal side effects Inhibits renal reabsption of glucose Targets: fasting BG values Contraindications/precautions Avoid use in egfr <45mL/min (canagliflozin, empagliflozin), <60mL/min (dapagliflozin) Active bladder cancer (dapagliflozin) Increased risk of ketoacidosis at baseline Adverse effects Common: genitourinary infections (7-8%), polyuria, volume depletion/hypotension/dizziness, increased LDL, increased creatinine (transient), hyperkalemia Rare: bone fractures (canagliflozin), bladder cancer (dapagliflozin), ketoacidosis, pyelonephritis, urosepsis, Increased amputations? Additional benefits Weight loss (~2kg) BP reduction (~2-4/1-2 mmhg) THE LEADER TRIAL Liraglutide vs. placebo in patients with cardiovascular(cv) risk and Type 2 Diabetes (T2DM) Approximately 9,000 patients with T2DM and Concomitant cardiovascular (80%), cerebrovascular, peripheral vascular disease chronic renal failure chronic heart failure HbA1c: 7.0% above Primary Outcome: Time from randomization to first occurrence of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke (a composite cardiovascular outcome) 13% relative risk reduction in cv death, nonfatal MI and nonfatal stroke (P=0.01) over 3 years 15% reduction in all cause mtality (P=0.02) on follow up 22% reduction in CV death (P=0.007) on follow up Number needed to treat to prevent one conary event over 3 years: 66 Number needed to treat to prevent one death: 98 THE EMPA-REG OUTCOME TRIAL Empagliflozin vs. placebo in patients with T2DM and established CV disease Composite: Hazard ratio 0.86 ( ); p=0.04 f superiity Driven by decreased CV death: 0.62 ( ) RCT of approximately 7000 patients Adults with T2DM and established cardiovascular disease Hemoglobin A1c 7-10%, BMI < 45 kg/m 2, egfr >30ml/min/1.73m 2 Placebo, empagliflozin 10mg, and empagliflozin 25mg over 3 years Primary Outcome: time to first occurrence of CV death, non-fatal MI, non-fatal stroke Accessed 6/15/

5 THE EMPA-REG OUTCOME TRIAL INSULIN ONSET AND DURATION Primary Outcome: Composite endpoint: 10.5% in empagliflozin vs. 12.2% in placebo group (NNT 62) Lower rates of death from CV causes (3.7% vs. 5.9% NNT 45) Reduced hospitalization f heart failure by 32% (2.7% vs. 4.1% NNT 71) All-cause mtality reduced by 38% (5.7% vs. 8.3% NNT 38) No difference in rates of MI stroke Adverse Events: Empagliflozin increased genital infections No difference in ketoacidosis fractures when compared to placebo Other: Little difference in efficacy between the 10mg and 25mg dose * Exhibits a peak at er dosages. Dose-dependent. 25 Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S CANAGLIFLOZIN UPDATE 5/2016 FDA repts interim safety concerns from ongoing trials showing increase in leg and foot amputations, mostly affecting the toes Canagliflozin Cardiovascular Assessment Study (CANVAS) identified increased risks of leg and foot amputations occurring nearly twice as often in canagliflozin vs placebo, followed f 4.5 years to date Second similar trial: CANVAS-R, has NOT shown the same amputation risks, followed f 9 months FDA recommendations: monit patients f new pain tenderness, ses ulcers, infections in legs and feet and notify their health care professional if any new concerns from above NEWER INSULIN FORMULATIONS Insulin Degludec U-100, U-200 Glargine U-300 Regular U-500 Humalog U-200 KwikPen INSULIN Kinetics Peakless Ultra-long acting; half life 25 hours After injection, degludec multi-hexamer assembles with zinc, then as zinc slowly diffuses, individual hexamers release into monomers that absb into circulation Daily dosing with flexible dosing window (8-40 hours) Less hypoglycemia (esp. nocturnal, T2DM) vs. glargine Fmulations: U100 pen (max 80 units/injection) U200 pen (max 160 units/injection) 70/30 combination with aspart pen INSULIN DEGLUDEC Tresiba.html?utm_source=bing_um&utm_medium=cpc&utm_content=Degludec&utm_campaign=tresiba_tresiba%202016%20 -%20FullLaunch_Tresiba%20General&utm_term=insulin%20degludec 30 5

6 INSULIN GLARGINE U-300 Tuojeo 300 units per ml; max 80 units per dose Compared to glargine U-100 Duration of action ~5 hours longer Maximum glucose lowering may take up to 5 days Smaller volume may results in reduced peak/trough ratio as compared to U-100 glargine Available in pen only INPATIENT DIABETES CARE 31 REGULAR INSULIN U units per ml Properties of sht and intermediate acting insulin Useful f patients with severe insulin resistance (>200 units daily) Typically given in 2-3 daily doses, 30 minutes befe meals, without additional basal prandial insulin Administration options: Vial with tuberculin/allergy syringe (ml) Insulin pen (Units) ; max 300 units per dose IMPACT OF HYPERGLYCEMIA AND DIABETES IN THE HOSPITAL The largest component of medical expenditures attributed to diabetes was hospital inpatient care (~50% of costs) Diabetes ranked #2, after circulaty diseases, as a hospital discharge diagnosis in ; Capes SE, et al. Lancet. 2000;355: Hyperglycemia on general medical surgical units is associated with 18-fold increase in in-hospital mtality Longer length of stay Me subsequent nursing home care Greater risk of infection %20Toujeo_General_MBR&utm_term=%20toujeo_ VQ16-c&moc=TJOCO23100WB 32 Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S HUMALOG U-200 QUIKPEN Bioequivalent to Humalog U-100 Twice the concentration of Humalog U-100 = half the volume per dose Contains 600 units of rapid-acting insulin compared with the 300 units in a U-100 pen Contains concentrated 200 units/ml insulin Disadvantages: Pen fmulation only, cost DIABETES CARE IN THE HOSPITAL: INSULIN Non-insulin antihyperglycemic agents have a limited role in acute-care settings Practitioners should consider discontinuing them in fav of insulin during acute illness The sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged. Patients treated with insulin befe admission should have their insulin dose modified accding to clinical status as a way of reducing the risk f hypoglycemia and hyperglycemia hcp.aspx?srcid=trusem_bing_humalogu200&wt.srch=1&wt.mc_id= &dclid=COuzl-ybqs0CFRaGaQod2pMLIA#about 33 Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S

7 INSULIN USE IN THE HOSPITAL The Joint Commission considers insulin 1of the 5 est-risk medicines in the inpatient setting The consequences of errs with insulin therapy can be catastrophic Insulin is consistently implicated in causing severe adverse events in hospitals through repting systems maintained by USP and ISMP Insulin omission Leads to hyperglycemia Po outcomes including increased risk of mtality Improper dose quantity of insulin Leads to hyperglycemia hypoglycemia Hyperglycemia ketoacidosis Hypoglycemia range of symptoms from nausea to falls to increased risk of myocardial ischemia A1C IS HELPFUL IN DETERMINING POST-DISCHARGE TREATMENT Patients With Previously Diagnosed Diabetes Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S CONDITIONS CREATING HIGH RISK FOR HYPOGLYCEMIA IN INPATIENTS ON INSULIN THE INPATIENT PHARMACISTS ROLE Sudden NPO status Unexpected transpt from nursing unit after rapid-acting insulin given Enteral feeding, TPN IV dextrose discontinued Premeal insulin given and meal not ingested Reduction of cticosteroid dose Minimizing medication errs Discouraging the use of sliding scale insulin Development of treatment protocols Fmulary decision-making Suppting the education of patients in advance of discharge Perfming admission / discharge medication reconciliation and educating patients on the changes Key areas of understanding: Treatment goals Treatment options Treatment protocols Potential medication errs and methods to reduce errs Imptance of pharmacy s role on the multidisciplinary team to ensure safe and effective management of hyperglycemia in the hospital setting Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S DIABETES CARE IN THE HOSPITAL: INPATIENT TO OUTPATIENT Imptance of medication reconciliation at discharge New, expired, discontinued medication changes documented Fill prescriptions f new changed medications at time of discharge befe patient leaves; consider fmulary preferred options & prescription insurance coverage f patient copay costs Education to patient AND family Questions Structured discharge communication Communicating medication changes, pending tests and studies and followup needs with primary care physician promptly Fward discharge summaries to primary care physicians Appointment compliance enhanced when inpatient team schedules outpatient follow-up Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S

8 REFERENCES Cohen MR. Am J Health-Syst Pharm. 2010;67(suppl 8):S17-S21. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metfmin in certain patients with reduced kidney function. (Accessed April 8, 2016) Moghissi ES, Kytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 2009;32: Clement S, Braithwaite SS, Magee MF, et al.;american Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004;27: CDC. National diabetes statistics rept, National Diabetes Surveillance System CDC. National diabetes fact sheet, Boyle JP, et al. Popul Health Metr Oct 22;8:29. Dall TM, et al. Diabetes Care. 2014;37: Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97: