What s New in Diabetes Medications? Matthew Kostoff, PharmD, BCPS, BCACP Clinical Assistant Professor Clinical Pharmacy Specialist Wesley Family Medicine Residency Program Objectives Discuss new literature for existing diabetes medications Explain a new class of diabetes medications and new dosage forms Differentiate between newly available diabetes medications to guide product selection Apply new evidence to patient population 1
Case Vignette You are seeing a new patient (68 y/o male) in your clinic to establish care. The main focus of his visit is regarding his Type II DM, which he currently takes metformin 1000 mg BID. He states he has been on this dose with no issues for over a year. Labs from today (no change from outside documents 3 months ago) Na = 140 meq/l, K+ = 4.4 meq/l, SCr = 1.6 mg/dl (egfr = 43 ml/min/1.73 m 2 ), BUN = 20 mg/dl, glucose = 99 mg/dl, A1c = 7.0% Which of the following would you do today in regards to the patient s metformin? A. Continue 1000 mg BID B. Discontinue C. Decrease dose to 500 mg BID D. Change to another oral agent 0% 0% 0% 0% A. B. C. D. Metformin and Kidney Function Contraindication in FDA labeling for use in: Men with SCr >1.5 mg/dl Women with SCr >1.4 mg/dl Risk of lactic acidosis Phenformin withdrawn from market in 1977 Label warnings applied to metformin despite difference in pharmacokinetics 2
Metformin Associated Lactic Acidosis Mild to moderate CKD reduces metformin clearance However, drug levels remain in safe range Circulating lactate levels are typically normal Frequency of lactic acidosis is low and similar to normal rates in overall diabetic population Less strict prescribing guidelines supported by professional societies Inzucchi, et al. JAMA. 2014 Dec 24 31;312(24):2668 75. Metformin Use vs. egfr 100 Metformin Use, 2011 2012, % 80 60 40 20 17.9 48.6 57.4 80.6 90.4 0 <30 30 to 45 >45 to 60 >60 to 90 >90 egfr, ml/min Flory, et al. JAMA Intern Med. 2015 Mar 1;175(3):458 9 3
Possible Approach CKD Stage egfr Max Daily dose, mg 1 >90 2550 2 60 <90 2550 3A 45 <60 2000 3B 30 <45 1000 4 15 <30 Do not use 5 <15 Do not use Inzucchi, et al. JAMA. 2014 Dec 24 31;312(24):2668 75. Back to the case You are seeing a new patient (68 y/o male) in your clinic to establish care. The main focus of his visit is regarding his Type II DM, which he currently takes metformin 1000 mg BID. He states he has been on this dose with no issues for over a year. Labs from today (no change from outside documents 3 months ago) Na = 140 meq/l, K+ = 4.4 meq/l, SCr = 1.6 mg/dl (egfr = 43 ml/min/1.73 m 2 ), BUN = 20 mg/dl, glucose = 99 mg/dl, A1c = 7.0% Which of the following would you do today in regards to the patient s metformin? A. Continue 1000 mg BID B. Discontinue C. Decrease dose to 500 mg BID D. Change to another oral agent 0% 0% 0% 0% A. B. C. D. 4
Metformin, then what? 2014 Sulfonylurea 2015 Sulfonylurea Thiazolidinedione Thiazolidinedione Metformin (+) DDP 4 inhibitor Metformin (+) DDP 4 inhibitor GLP 1 agonist SGLT2 inhibitor Basal insulin GLP 1 agonist Basal insulin Inzucchi, et al. Diabetes Care. 2015 Jan;38(1):140 9. SGLT2 INHIBITORS 5
Pharmacology Glucose SGLT2 S1 segment of proximal tubule ~90% reabsorption S2/S3 segment of proximal tubule SGLT1 Collecting duct ~10% reabsorption SGLT = Sodium Glucose Cotransporter No Glucose Choa, et al. Nat Rev Drug Discov. 2010 Jul;9(7):551 9. Efficacy and Safety Advantages ~0.7 1% A1c reduction Low risk of hypoglycemia Disadvantages Genital mycotic infections and urinary tract infections Weight loss (~1 3 kg) Reduction in systolic BP (~3 5 mmhg) Monitor volume status and electrolytes 6
Available Products Canagliflozin (Invokana) Initial dose (PO) 100 mg daily prior to first meal Dapaglifozin (Farxiga) 5 mg daily in morning Empaglifozin (Jardiance) 10mg daily Max dose 300 mg daily 10 mg daily 25 mg daily Renal dose adjustments (egfr) 45 <60mL/min: 100mg daily <45mL/min: Not recommended <60mL/min: Not recommended <45mL/min: Not recommended Combo product available w/ metformin (Invokamet) w/ metformin ER (Xigduo XR) w/ linagliptin (Glyxambi) Metformin, then Sulfonylurea Thiazolidinedione Metformin (+) DDP 4 inhibitor SGLT2 inhibitor GLP 1 agonist Basal insulin 7
GLP 1 AGONISTS Pharmacology Brain appetite Liver glucose production GLP 1 Pancreas b cell proliferation b cell apoptosis insulin secretion glucagon secretion Muscle Stomach insulin sensitivity gastric emptying 8
Available Options Medication Brand Name FDA Approval Exenatide Dosing Frequency Byetta April 2005 Twice daily Bydureon January 2012 Weekly Liraglutide Victoza January 2010 Daily Albiglutide Tanzeum April 2014 Weekly Dulaglutide Trulicity September 2014 Weekly Lixisenatide Withdrawn 2012, Resubmitted 2013 Daily Comparative A1c Reduction Change in A1c (%) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Chart Title LEAD 6 DURATION 5 DURATION 6 HARMONY 7 AWARD 6 Exenatide BID Liraglutide Exenatide BID Exenatide QW Exenatide QW Liraglutide Albiglutide Liraglutide Dulaglutide Liraglutide Exenatide BID Exenatide QW Liraglutide Albiglutide Dulaglutide Trujillo, et al. Ther Adv Endocrinol Metab. 2015 Feb;6(1):19 28. 9
Change in Weight (Kg) 0 0.5 1 1.5 2 2.5 3 3.5 4 Comparative Weight Loss Chart Title LEAD 6 DURATION 5 DURATION 6 HARMONY 7 AWARD 6 Exenatide BID Liraglutide Exenatide BID Exenatide QW Exenatide QW Liraglutide Exenatide BID Exenatide QW Liraglutide Albiglutide Dulaglutide Albiglutide Liraglutide Dulaglutide Liraglutide Trujillo, et al. Ther Adv Endocrinol Metab. 2015 Feb;6(1):19 28. Safety and Counseling Injection site reactions GI side effects Titrate dose Eat smaller meals Weekly vs. Daily Need pen needle prescription with daily products Dulaglutide easiest instructions for weekly products Others require reconstitution by patient 3 day grace period with weekly options 10
Metformin, then Sulfonylurea Thiazolidinedione Triple Therapy Metformin (+) DDP 4 inhibitor SGLT2 inhibitor GLP 1 agonist Basal insulin OR Basal Insulin plus Mealtime Insulin or GLP 1 Agonist GLP 1 agonist combo with Basal Insulin Meta analysis of 15 studies examined efficacy and safety of combination Achievement of the ideal trifecta? Glycemic control, no hypoglycemia, no weight gain Eng,et al. Lancet. 2014 Dec 20;384(9961):2228 34. 11
GLP 1 agonist combo with Basal Insulin Primary Endpoints Reduction in A1c (%) vs. any treatment Reduction in weight (kg) vs. any treatment Proportion achieving A1c <7% vs. any treatment Incidence of hypoglycemia vs. any treatment Weighted mean difference (95% CI) 0.44 ( 0.60 to 0.29) 3.22 ( 4.90 to 1.54) Relative Risk (95% CI) 1.92 (1.43 2.56) 0.99 (0.76 1.29) Long term safety and durability not examined Eng,et al. Lancet. 2014 Dec 20;384(9961):2228 34. INHALED INSULIN 12
Inhaled Insulin Alternative administration routes of insulin has been an area of research for years Exubera introduced to market in 2006, withdrawn in 2007 Dosing in milligrams Large inhaler device Technosphere Insulin (Afrezza) Approved July 2014 Contains recombinant human insulin in a dry powder Faster absorption, though no difference in onset of action Kugler, et al. Pharmacotherapy. 2015 Mar;35(3):298 314 Images available at: http://www.mannkindcorp.com/news and events media room photos.htm 13
Dosing Conversion Injected Bolus Insulin Dose < 4 units 5 8 units 9 12 units 13 16 units 17 20 units 21 24 units Recommended Inhaled Insulin Dose 4 units 8 units 12 units 16 units 20 units 24 units Available in single cartridges of either 4 or 8 unit strengths Kugler, et al. Pharmacotherapy. 2015 Mar;35(3):298 314 Pulmonary Safety Patients should undergo spirometry testing at baseline, 6 months and annually Not recommended for: COPD Asthma Smokers (or recently stopped) Kugler, et al. Pharmacotherapy. 2015 Mar;35(3):298 314 14
Patient Education Refrigerate cartridges not in use At room temperature: sealed cartridge should be used within 10 days, unsealed within 3 days Cartridges should be kept at room temperature for >10 minutes before use Dispose of device after 15 days and replace Kugler, et al. Pharmacotherapy. 2015 Mar;35(3):298 314 Role in Therapy Alternative for patients seeking noninvasive therapy Bolus insulin alone not a current standard of care Patients on basal insulin less likely to be averse to injections or needles 15
Future Considerations for Insulin Toujeo (insulin glargine) U 300 strength Approved February 2015 Insulin Degludec Ultra long acting insulin Approved in other countries Duration of action up to 42 hours What s New with Diabetes Medications Metformin and CKD Advocacy for labeling changes SGLT2 Inhibitors Increased urinary glucose excretion Increased risk of infections GLP 1 Agonists Newer weekly products on market Consider combo with basal insulin Inhaled Insulin Afrezza available, unclear role in therapy 16
Questions? mkostoff@ku.edu 17