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

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Type 2 Diabetes: Latest Drug Approvals and Use of the Newer Agents 9/24/2017 Type 2 Diabetes: Latest Drug Approvals and Use of the Newer Agents Gretchen Ray, PharmD, PhC, BCACP, CDE Associate Professor, UNM College of Pharmacy October 9th, 2017 [email protected] OBJECTIVES •Describe the recently approved insulins •Compare and contrast the GLP-1 receptor agonists and the recent literature supporting this drug class •Describe the available SGLT2 inhibitors and the efficacy and safety profile of this drug class 1 9/24/2017 UPDATED GUIDELINES •Standards of Medical Care in Diabetes 2017. Diabetes Care 2017;40(Suppl 1) Canagliflozin Alogliptin 2013 Dapagliflozin Empagliflozin Albiglutide DIABETES MEDICATIONS Dulaglutide Afrezza inhaled insulin 2014 U-300 Glargine Linagliptin Insulin Degludec 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 2 9/24/2017 TYPES OF INSULIN • Rapid Acting • Humalog® (lispro) (U-100 and U-200) • Novolog ® (aspart) • Apidra ® (glulisine) • Short Acting-Regular Insulin (R) • Novolin® R • Humulin® R • Intermediate Acting-NPH (N) • Novolin® N • Humulin ® N • Long Acting – Basal Insulin • Levemir® (detemir) • Lantus®/Basaglar ® (U-100 glargine) • Toujeo® (U-300 glargine) • Tresiba®(Degludec U-100 and U-200) INSULIN GLARGINE 300 UNITS/ML (TOUJEO® SOLOSTAR PEN) • Higher concentration of Insulin Glargine • Only available in pen form • Lasts slightly longer than 24 hours • Converting from U-100 Glargine to U-300 Glargine • 1:1 then titrate up • Typically a higher dose of Toujeo® is required • Converting from U-300 Glargine to U-100 Glargine • Use 80% of the dose of Toujeo® Toujeo. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 12, 2017 3 9/24/2017 EDITION CLINICAL TRIAL SERIES. GLARGINE U-300 VS. U-100 HYPOGLYCEMIA RISK • U-300 led to 21% relative risk reduction of ≥ 1 hypoglycemic event from week 9 to month 6 EDITION 1 (p=0.0045)1 • U-300 led to 23% relative risk reduction of ≥ 1 hypoglycemic event from week 9 to month 6 EDITION 2 (p=0.038)2 • 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 3Diabetes Obes Metab. 2015;17 META-ANALYSIS OF EDITION 1, 2, AND 3 •Slightly less weight gain with U-300 vs. U-100 • LS mean difference -0.28, 95% CI -0.55 to -0.01 •Higher mean basal insulin dose at month 6 in the U-300 group • 0.85 units/kg/day U-300 vs. 0.76 units/kg/day U- 100 •Comparable A1C reduction in both groups Ritzel R, et al. Diabetes Obesity and Metabolism. 2015 4 9/24/2017 INSULIN DEGLUDEC (TRESIBA®) •Ultra-Long-acting basal insulin •Duration up to 42 hours •Injected once a day at any time of day •U-100 and U-200 strengths •Available only as a FlexTouch® Pen Tresiba. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 12, 2017 DEVOTE: EFFICACY AND SAFETY OF DEGLUDEC VS. GLARGINE IN TYPE 2 DIABETES •Primary Outcome: first occurrence of cardiovascular death, non-fatal MI, or non- fatal stroke •Secondary: number of severe hypoglycemic episodes, time from randomization to MACE + time to hospitalization for unstable angina pectoris, number of serious adverse events, AEs leading to discontinuation of treatment drug. Marso SP, et al. NEJM. 2017;377(8):723-32 5 9/24/2017 DEVOTE: EFFICACY AND SAFETY OF DEGLUDEC VS. GLARGINE IN TYPE 2 DIABETES • Duration of follow-up: 1.99 years • Mean patient age: 65 years • Diabetes duration: 16.4 years •Key inclusion criteria: • adult patients with type 2 diabetes, age ≥ 50 years with predefined previous CVD or renal disease • 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 DEVOTE: EFFICACY AND SAFETY OF DEGLUDEC VS. GLARGINE IN TYPE 2 DIABETES Outcome Degludec Glargine Ratio (95% CI), P- NNT (no./100 pt (no./100 pt value years) year) Primary 4.29 4.71 HR 0.91(0.78-1.06) Composite P<0.001 for non- inferiority Severe 3.7 6.25 RR 0.60(0.48-0.76) 39 Hypoglycemia p<0.001 for superiority Marso SP, et al. NEJM. 2017;377(8):723-32 6 9/24/2017 LONG ACTING INSULIN PREPARATIONS Pen/vial Pen Storage of in Max Dose Pen Dose Volume Package use pen or vial Pen can increment Size at room temp Dial/injection Tresiba® 3 mL (300 5 pens 56 Days 80 units 1 unit units) FlexTouch® U-100 Tresiba® 3 mL (600 3 pens 56 Days 160 units 2 units units) FlexTouch® U-200 Toujeo® U- 1.5 mL (450 3 or 5 42 Days 80 units 1 unit units) 300 pens Lantus® 3 mL (300 5 pens 28 Days 80 units 1 unit units) or 1 vial (1000 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) COUNSELING CONSIDERATIONS •New concentrations of Glargine U-300, Degludec U-200, and now Insulin Lispro (Humalog®) U-200 • Caution patients not to use syringes to draw insulin our of their pens •Different storage criteria of in use pen for each product •Maximum dose each pen can dial up to 7 9/24/2017 GLP-1 Receptor Agonists GLP-1 Secretion and Inactivation Mixed meal Intestinal GLP-1 release T1/2= 1 to 2 min GLP-1 active DPP-4 GLP-1 inactive (>80% of pool) 8 9/24/2017 GLP-1 PHYSIOLOGY GLP-1 secreted upon the ingestion of food EXENATIDE (BYETTA®) •Dosing: • 5 mcg SC twice daily within 60 min of start of a meal • Increase to 10 mcg bid after 4 weeks • Need to prescribe pen needles 9 9/24/2017 LIRAGLUTIDE (VICTOZA®) • Dosing: 0.6 mg SQ once daily x 1 week • Then 1.2 mg SQ daily x 1 week • 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®) EXENATIDE LONG ACTING (BYDUREON®) •2 mg subq once a week • Without regard to meals or time of day 10 9/24/2017 ALBIGLUTIDE (TANZEUM™) •Will no longer be on the market as of 2018 DULAGLUTIDE (TRULICITY™) • 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 11 9/24/2017 FUTURE GLP-1 AGONISTS •Semaglutide: once weekly injectable and daily oral formulation in trials GLP-1 AGONIST ADVERSE EFFECTS/PRECAUTIONS •Adverse Effects •Contraindications/Pr • 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 12 9/24/2017 GLP-1 AGONIST BENEFITS •Low risk of hypoglycemia • Slightly higher risk when used with 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) GLP-1 RA CV Safety Trials 13 9/24/2017 LEADER: LIRAGLUTIDE EFFECT AND ACTION IN DIABETES: EVALUATION OF CARDIOVASCULAR OUTCOME RESULTS • Evaluated liraglutide vs. placebo + standard of care in patients with type 2 diabetes and high risk of CV disease or with established CV disease • Median follow-up 3.8 years • Primary outcome: first occurance of death from CV cause, non-fatal MI or non-fatal stroke •Primary outcome occurred in 13.0% liraglutide vs. 14.9% in placebo group (p<0.001 for noninferiority; p=0.01 for superiority) N Engl J Med 2016;375:311-22 SUSTAIN-6: SEMAGLUTIDE CV SAFETY TRIAL 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. They were followed for a median of 2.1 years. Results 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 superiority • 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 • HbA1c at week 104: 7.6% vs. 7.3% vs. 8.3% % Conclusions • Injectable once a week semaglutide (GLP-1 agonist) was superior to Primary outcome placebo in improving glycemic control and ↓ CV events in high-risk patients Semaglutide Placebo with diabetes (n = 1,648) (n = 1,649) Marso SP, et al. N Engl J Med 2016;375:1834-44 14 9/24/2017 GLP-1 RA CV STUDIES DEMONSTRATING NON-INFERIORITY •ELIXA1-lixisenatide •EXSCEL2- exenatide LAR 1. Pfeffer MA, et al. NEJM. 2015;373(23):2247-57 2. Holman RR, et al. NEJM. 2017 Sept 14; epub ahead of print GLP-1 Agonist/Basal Insulin Combination Pens 15 9/24/2017 INSULIN GLARGINE & LIXISENATIDE (SOLIQUA™ 100/33 SOLOSTAR® PENS) • Combination of insulin glargine 100 units/mL and lixisenatide 33 mcg/mL • Available in pen form • 1 box = 5 pens = 1500 units • Approved for patients uncontrolled on a basal insulin • Once daily dosing • Dosing: • Patients on <30 units basal insulin: start 15 units of Soliqua™ 100/33 • Patients on >30 units basal insulin: start 30 units of Soliqua™ 100/33 • Titration is similar to basal insulin alone…increase by 2- 4 units/week until fasting glucose <130 mg/dL • Max dose is 60 units • If patient
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