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Type 2 Diabetes: Latest Drug Approvals and Use of the Newer

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Type 2 Diabetes: Latest Drug Approvals and Use of the Newer 9/24/2017 OBJECTIVES Type 2 Diabetes: Latest •Describe the recently approved insulins Drug Approvals and Use •Compare and contrast the GLP-1 receptor agonists and the recent literature supporting of the Newer Agents this drug class •Describe the available SGLT2 inhibitors and Gretchen Ray, PharmD, PhC, BCACP, CDE the efficacy and safety profile of this drug Associate Professor, UNM College of class Pharmacy October 9th, 2017 [email protected] Canagliflozin Alogliptin 2013 Dapagliflozin Empagliflozin Albiglutide UPDATED GUIDELINES DIABETES MEDICATIONS Dulaglutide Afrezza inhaled insulin •Standards of Medical Care in Diabetes 2017. 2014 U-300 Glargine Linagliptin Insulin Degludec Diabetes Care 2017;40(Suppl 1) Basaglar 2011 2015 Insulin Metformin 1922 Sitagliptin AGIs Saxagliptin SUs 2006 1995 2009 1957 1960 1995 2000 2005 2010 2015 Glinides Exenatide Liraglutide TZDs Pramlintide 2010 1997 2005 2012 Exenatide LAR INSULIN GLARGINE 300 UNITS/ML TYPES OF INSULIN (TOUJEO® SOLOSTAR PEN) • Rapid Acting • Higher concentration of Insulin Glargine • Humalog® (lispro) (U-100 and U-200) • Novolog ® (aspart) • Only available in pen form • Apidra ® (glulisine) • Short Acting-Regular Insulin (R) • Lasts slightly longer than 24 hours • Novolin® R • Converting from U-100 Glargine to U-300 • Humulin® R Glargine • Intermediate Acting-NPH (N) • Novolin® N • 1:1 then titrate up • Humulin ® N • Typically a higher dose of Toujeo® is required • Long Acting – Basal Insulin • Converting from U-300 Glargine to U-100 • Levemir® (detemir) • Lantus®/Basaglar ® (U-100 glargine) Glargine • Toujeo® (U-300 glargine) • Use 80% of the dose of Toujeo® • Tresiba®(Degludec U-100 and U-200) Toujeo. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 12, 2017 1 9/24/2017 EDITION CLINICAL TRIAL SERIES. GLARGINE U-300 VS. U-100 HYPOGLYCEMIA RISK META-ANALYSIS OF EDITION 1, 2, AND 3 •Slightly less weight gain with U-300 vs. U-100 • U-300 led to 21% relative risk reduction of ≥ 1 hypoglycemic event from week 9 to month 6 • LS mean difference -0.28, 95% CI -0.55 to -0.01 EDITION 1 (p=0.0045)1 •Higher mean basal insulin dose at month 6 in the U-300 group • U-300 led to 23% relative risk reduction of ≥ 1 hypoglycemic event from week 9 to month 6 • 0.85 units/kg/day U-300 vs. 0.76 units/kg/day U- EDITION 2 (p=0.038)2 100 •Comparable A1C reduction in both groups • Similar rate of hypoglycemia from week 9 to 3 EDITION 3 month 6 in both groups (p=0.45) 1Diabetes Care. 2014;37(10):2755-2762 2Diabetes Care. 2014;37(12):3235-3243 Ritzel R, et al. Diabetes Obesity and Metabolism. 2015 3Diabetes Obes Metab. 2015;17 DEVOTE: EFFICACY AND SAFETY OF DEGLUDEC INSULIN DEGLUDEC (TRESIBA®) VS. GLARGINE IN TYPE 2 DIABETES •Ultra-Long-acting basal insulin •Primary Outcome: first occurrence of •Duration up to 42 hours cardiovascular death, non-fatal MI, or non- fatal stroke •Injected once a day at any time of day •Secondary: number of severe •U-100 and U-200 strengths hypoglycemic episodes, time from •Available only as a FlexTouch® Pen randomization to MACE + time to hospitalization for unstable angina pectoris, number of serious adverse events, AEs leading to discontinuation of treatment drug. Tresiba. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, Marso SP, et al. NEJM. 2017;377(8):723-32 IL. Available at: http://online.lexi.com. Accessed September 12, 2017 DEVOTE: EFFICACY AND SAFETY OF DEGLUDEC DEVOTE: EFFICACY AND SAFETY OF DEGLUDEC VS. GLARGINE IN TYPE 2 DIABETES VS. GLARGINE IN TYPE 2 DIABETES • Duration of follow-up: 1.99 years • Mean patient age: 65 years Outcome Degludec Glargine Ratio (95% CI), P- NNT (no./100 pt (no./100 pt value • Diabetes duration: 16.4 years years) year) •Key inclusion criteria: Primary 4.29 4.71 HR 0.91(0.78-1.06) Composite P<0.001 for non- • adult patients with type 2 diabetes, age ≥ 50 inferiority years with predefined previous CVD or renal Severe 3.7 6.25 RR 0.60(0.48-0.76) 39 disease Hypoglycemia p<0.001 for superiority • OR age ≥ 60 years with at least one predefined CV risk factor • A1C ≥ 7.0% or A1C < 7.0% and current insulin treatment corresponding to ≥ 20 units basal insulin per day; and patients on one or more oral or injectable antidiabetic agent(s). Marso SP, et al. NEJM. 2017;377(8):723-32 Marso SP, et al. NEJM. 2017;377(8):723-32 2 9/24/2017 LONG ACTING INSULIN PREPARATIONS COUNSELING CONSIDERATIONS Pen/vial Pen Storage of in Max Dose Pen Dose Volume Package use pen or vial Pen can increment •New concentrations of Glargine U-300, Dial/injection Size at room temp Degludec U-200, and now Insulin Lispro Tresiba® 3 mL (300 5 pens 56 Days 80 units 1 unit units) ® FlexTouch® (Humalog ) U-200 U-100 Tresiba® 3 mL (600 3 pens 56 Days 160 units 2 units • Caution patients not to use syringes to draw units) FlexTouch® insulin our of their pens U-200 Toujeo® U- 1.5 mL (450 3 or 5 42 Days 80 units 1 unit •Different storage criteria of in use pen for units) 300 pens each product Lantus® 3 mL (300 5 pens 28 Days 80 units 1 unit units) or 1 vial (1000 •Maximum dose each pen can dial up to units) Basaglar® 3mL (300 5 Pens 28 days 80 units 1 unit units) KwikPens Levemir® 3 mL (300 5 pens 42 Days 80 units 1 unit units) or 1 vial (1000 units) GLP-1 Secretion and Inactivation Mixed meal Intestinal GLP-1 GLP-1 Receptor Agonists release T1/2= 1 to 2 min GLP-1 active DPP-4 GLP-1 inactive (>80% of pool) GLP-1 PHYSIOLOGY EXENATIDE (BYETTA®) •Dosing: • 5 mcg SC twice daily within 60 min of start of a meal GLP-1 secreted upon the ingestion of food • Increase to 10 mcg bid after 4 weeks • Need to prescribe pen needles 3 9/24/2017 ® LIRAGLUTIDE (VICTOZA ) EXENATIDE LONG ACTING (BYDUREON®) • Dosing: 0.6 mg SQ once daily x 1 week •2 mg subq once a week • Then 1.2 mg SQ daily x 1 week • Without regard to meals or time of day • Can increase to 1.8 mg daily if needed • Timing of doses, independent of meals • Need to prescribe pen needles • Liraglutide is also FDA approved for obesity in a 3 mg once a day dose (Saxenda®) ALBIGLUTIDE (TANZEUM™) DULAGLUTIDE (TRULICITY™) •Will no longer be on the market as of 2018 • 0.75 mg SQ once weekly • Can increase to 1.5 mg once weekly • Each pen is single use • Patient does not see the needle when performing the injection • No mixing steps when performing the injection • No renal adjustments GLP-1 AGONIST ADVERSE FUTURE GLP-1 AGONISTS EFFECTS/PRECAUTIONS •Semaglutide: once weekly injectable and •Adverse Effects •Contraindications/Pr daily oral formulation in trials • Nausea and vomiting – ecautions most common AE • Type 1 diabetes • Anti-exenatide antibodies • Very rare • Gastroparesis • Cases of acute • History of pancreatitis pancreatitis • History of medullary thyroid carcinoma • Multiple endocrine neoplasia syndrome 2 4 9/24/2017 GLP-1 AGONIST BENEFITS •Low risk of hypoglycemia • Slightly higher risk when used with GLP-1 RA CV Safety Trials sulfonylureas or insulin •Weight loss •Potential for once daily or once weekly dosing •Studies have shown addition to a basal insulin can be as effective as starting a pre- meal insulin – see ADA insulin dosing algorithm Standards of Medical Care in Diabetes 2017. Diabetes Care 2017;40(Suppl 1) LEADER: LIRAGLUTIDE EFFECT AND ACTION IN DIABETES: SUSTAIN-6: SEMAGLUTIDE CV SAFETY TRIAL EVALUATION OF CARDIOVASCULAR OUTCOME RESULTS Trial design: Patients with DM2 at high risk for CV events were randomized in a 1:1:1:1 fashion to either semaglutide 0.5 mg, semaglutide 1 mg, or matching placebo. • Evaluated liraglutide vs. placebo + standard of They were followed for a median of 2.1 years. care in patients with type 2 diabetes and high risk Results of CV disease or with established CV disease pnoninferiority < 0.001 p = 0.02 • Primary outcome, CV death/MI/stroke: semaglutide superiority vs. placebo: 6.6% vs. 8.9%, HR 0.74, 95% CI 0.58- 0.95, p < 0.001 for noninferiority; p = 0.02 for • Median follow-up 3.8 years superiority • Primary outcome: first occurance of death from • CV death: 2.7% vs. 2.8%, p = 0.92; all MI: 2.9% vs. 3.9%, p = 0.12; all stroke: 1.6% vs. 2.7%, p = 0.04 CV cause, non-fatal MI or non-fatal stroke • HbA1c at week 104: 7.6% vs. 7.3% vs. 8.3% % •Primary outcome occurred in 13.0% Conclusions liraglutide vs. 14.9% in placebo group • Injectable once a week semaglutide (p<0.001 for noninferiority; p=0.01 for (GLP-1 agonist) was superior to Primary outcome placebo in improving glycemic control superiority) and ↓ CV events in high-risk patients Semaglutide Placebo with diabetes (n = 1,648) (n = 1,649) N Engl J Med 2016;375:311-22 Marso SP, et al. N Engl J Med 2016;375:1834-44 GLP-1 RA CV STUDIES DEMONSTRATING NON-INFERIORITY •ELIXA1-lixisenatide GLP-1 Agonist/Basal Insulin •EXSCEL2- exenatide LAR Combination Pens 1. Pfeffer MA, et al. NEJM. 2015;373(23):2247-57 2. Holman RR, et al. NEJM. 2017 Sept 14; epub ahead of print 5 9/24/2017 INSULIN GLARGINE & LIXISENATIDE INSULIN DEGLUDEC AND LIRAGLUTIDE (SOLIQUA™ 100/33 SOLOSTAR® PENS) (XULTOPHY™ 100/3.6) • Combination of insulin glargine 100 units/mL and •100 units Insulin degludec + 3.6 mg lixisenatide 33 mcg/mL liraglutide/mL • Available in pen form • 1 box = 5 pens = 1500 units •Dose range 16-50 units once a day • Approved for patients uncontrolled on a basal insulin • Once daily dosing • Start patients on 16 units once a day • Dosing: • Titrate by 2 units every 3-4 days until fasting glucose at goal • Patients on <30 units basal insulin: start 15 units of Soliqua™ 100/33 • Max dose 50 units (=50 units degludec + 1.8 • Patients on >30 units basal insulin: start
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