Updates in Diabetes Care

Transcription

1 Updates in Diabetes Care Disclosures Nothing to disclose Pharmacist Objectives 1. List strategies for improving diabetes care 2. Understand benefits and risks associated with newer pharmacotherapeutic agents used to treat diabetes mellitus 3. Discuss investigational drugs that may be available for the treatment of diabetes mellitus in the near future Technician Objectives 1. Understand what an A1C measures and how it correlates to blood glucose 2. Recognize A1C and blood glucose values that are not at goal 3. Classify medications used to treat diabetes mellitus Estimates of Diagnosed Diabetes among Adults 20 years old Estimated Diabetes Costs in the United States, 2012 Direct $ 176 billion Indirect $69 billion Total cost $ 245 billion Accessed 9/4/15. diabetes report web.pdf. Accessed 9/4/15. 1

2 Impaired Secr Hyperglycemia Insulin etionincrease IncreH Decre ased GP Impa S ecretion iredinsulin Li Hyperg HGP lycemia DecreasedGUptak 9/11/2015 Type 1 Diabetes Type 2 Diabetes Non Modifiable Risk Factors Genetics Age Ethnicity Modifiable Risk Factors Overweight/obese Hypertension Hyperlipidemia History of gestational diabetes, polycystic ovarian syndrome, cardiovascular disease of diabetes/type1/understanding type 1 diabetes/what is type 1 diabetes/ Accessed 9/4/15. Glucagon Secretion Decreased Insulin Secretion Hepatic Glucose Production Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58: Copyright 2009 American Diabetes Association. All rights reserved. Decreased Incretin Effect HYPERGLYCEMIA Neurotransmitter Dysfunction Lipolysis Decreased Glucose Uptake Glucose Reabsorption Type 2 Diabetes 1. Alpha glucosidase inhibitor 2. Amylin analog 3. Biguanide 4. Bile acid sequestrant 5. Dipeptidyl peptidase 4 (DPP 4) inhibitor 6. Glucagon like, peptide 1 (GLP 1) agonist 7. Insulin 8. Meglitinide 9. Sodium glucose co transporter 2 (SGLT2) inhibitor 10. Sulfonylurea 11. Thiazolidinedione (TZD) 12. Dopamine agonist Type 1 & Type 2 Diabetes 1. Amylin analog 2. Insulin Type 2 Diabetes Pharmacotherapy Insulin, Sulfonylureas GLP 1 agonists, DPP 4 inhibitors GLP 1 agonists, DPP 4 inhibitors Glucagon Secretion Decreased Insulin Secretion Hepatic Glucose Production Biguanides GLP 1 agonists, DDP 4 Inhibitors Decreased Incretin Effect HYPERGLYCEMIA Neurotransmitter Dysfunction Lipolysis Decreased Glucose Uptake TZDs Glucose Reabsorption TZDs SGLT 2 Inhibitors Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58: Copyright 2009 American Diabetes Association. All rights reserved. Diagnosis Diabetes Care 2015;38(Suppl. 1):S8 S16 2

3 Hemoglobin A1C Glycemic Control & Complications Diagnose and assess control of diabetes Percent hemoglobin in red blood cells that is glycated Average glucose over previous 2 3 months DCCT UKPDS ACCORD ADVANCE VADT Microvascular Macrovascular Mortality Accessed 9/4/15. DCCT Group. N Engl J Med 1993;329: UKPDS Group. Lancet 1998;352: Gerstein et al. New Engl J Med 2008;358: Patel et al. New Engl J Med 2008;358: Duckworth et al. New Engl J Med 2009;360: ADA AACE A1C <7.0% 6.5% Preprandial glucose mg/dl <110 mg/dl Postprandial glucose <180 mg/dl <140 mg/dl Diabetes Care 2015;38(Suppl. 1):S33 S40. Endocr Pract.2015;21: Diabetes Care 2015;38(Suppl. 1):S33 S40 Rates of Diabetes Control Strategies to Improve Care 60% 50% 40% 30% 44% Percent of Patients with A1C < 7.0% 57% 52.5% Optimize Provider and Team Behavior Support Patient Behavior Change 20% 10% 0% Change the Care System Diabetes Care Aug;36(8): Diabetes Care 2015;38(Suppl. 1):S5 S7 3

4 Diabetes Care 2015;38(Suppl. 1):S41 S48 complications/. Accessed 9/4/15. DPP 4 Inhibitors Cobble, M. J Fam Pract October;58(10). Type 2 Diabetes Drugs and MACE International regulatory agencies require all new antihyperglycemic agents exclude clinically meaningful increases in major adverse cardiovascular events (MACE) FDA: Sponsors should demonstrate that the therapy will not result in unacceptable increase in CV risk. MACE CV death, non fatal MI, non fatal stroke MACE+ Hospitalization for acute coronary syndrome, urgent revascularization procedures, or other endpoints SAVOR TIMI 53 16,492 patients with type 2 diabetes who had a history of/at risk for CV events received saxagliptin or placebo Median f/u 2.1 years No difference in primary end point: composite of CV death, nonfatal MI, or nonfatal ischemic stroke 613 patients (7.3%) in the saxagliptin group 609 patients in the placebo group (7.2%) Hazard ratio, 1.00; 95% CI, 0.89 to 1.12, P<0.001 for noninferiority; p=0.99 for superiority More patients treated with saxagliptin were hospitalized for HF compared to placebo (3.5% vs 2.8%, hazard ratio 1.27, 95 CI 1.07 to 1.51, p=0.007, NNH 143) Accessed 9/4/15. Scirica, et al. N Engl J Med 2013; 369:

5 EXAMINE TECOS 5,380 patients with type 2 diabetes with history of or at risk for CV events received alogliptin or placebo Median f/u 18 months No difference in primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke 11.3% of patients in the alogliptin group 11.8% of patients in the placebo group Hazard ratio, 0.96; upper boundary of the one sided repeated CI, 1.16; P<0.001 for noninferiority; P = 0.32 for superiority Hospital admission for heart failure was the first event in 85 (3 1%) patients taking alogliptin compared with 79 (2 9%) taking placebo (HR 1 07, 95% CI ) No effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1 00, 95% CI ) No significant difference in incidence of acute or chronic pancreatitis or pancreatic cancer 14,671 patients had either sitagliptin or placebo added to their existing therapy Median f/u 3 years No difference in primary endpoint 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person years). Sitagliptin found to be noninferior (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). No difference in hospitalizations for heart failure (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). No significant differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32) N Engl J Med 2013; 369: N Engl J Med 2015; 373: DPP 4 Inhibitors New warning for severe joint pain Added to PI and medication guide Onset of symptoms 1 day to years after they starting Symptoms relieved upon drug discontinuation Some patients developed severe joint pain again when they restarted the same or another DPP 4 inhibitor Accessed 9/4/15. DJ Drucker. Cell Metab. 2006;3: GLP 1 Agonists SGLT 2 Inhibitors Available agents Exenatide, Exenatide LAR, liraglutide, albiglutide, dulaglutide Efficacy High, 1 1.5% A1c reduction ADRs Nausea Diarrhea May be associated with pancreatitis May be associated with renal insufficiency Associated with thyroid cell cancer in rodents Effect on weight Loss Hypoglycemia risk Low Renal/Hepatic Do not use exenatide if egfr < 30mL/min Cost High, $ /month Blocks transporter responsible for reabsorbing majority of glucose filtered by kidney Increases urinary glucose excretion Lowers blood glucose Pharmacist's Letter 2014; 30(10): Accessed 9/4/15. 5

6 Renal Handling of Glucose Adapted from: Bailey CJ. Trends in Pharmacol Sci 2011;32: Chao EC. Core Evidence 2012;7: SGLT = Sodium dependent glucose transporter 31 Adapted from: Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9: DeFronzo RA, et al. Diab Obes Metab 2012;14:5 14. Washburn WN. J Med Chem 2009;52: SGLT 2 Inhibitors Available agents Canagliflozin, dapagliflozin, empagliflozin Efficacy Intermediate, ~ 1% A1c reduction ADRs Mycotic urinary tract infections Hypotension LDL and non HDL cholesterol Decreased bone mineral density and of increased bone turnover Dapagliflozin may be associated with increased risk of bladder cancer Canagliflozin may be associated with increased risk of stroke Effect on weight Loss Hypoglycemia risk Low Renal/Hepatic Do not use canagliflozin, empagliflozin if egfr <45 ml or dapagliflozin if egfr <60 ml Cost High; >$300 / month Development of Euglycemic DKA BG mildly high further insulin Rapid development of eudka ketones = nausea, caloric intake, volume depletion Worsened by insulin and carb intake SGLT2 Inhibitors lipid oxidation, lipolysis and glucagon mobilization of FFA and TGs ketogenesis β hydroxylbutyrate Pharmacist's Letter 2014; 30(10): Accessed 9/4/15. Adapted from Rosenstock and Ferrannini. Dia Care 2015;38: Incidence of eudka with Canagliflozin Inhaled Insulin Incidence Rate per 1000 Patient Years Onset Peak Duration Administration How supplied Dose conversion Stability at room temperature Cost minutes 53 minutes 160 minutes Route: oral inhalation Timing: beginning of a meal 4 and 8 unit single use cartridges Round each mealtime insulin dose up to the nearest 4 units, then convert unit per unit Opened strips stable: 3 days Unopened foil packs, blister cards, and strips: 10 days Inhaler: 15 days High; varies based on dose 0 Canagliflozin 100mg Canagliflozin 300mg Comparator Adapted from Rosenstock and Ferrannini. Dia Care 2015;38: Pharmacist's Letter 2014; 30(6): Pharmacist's Letter 2015; 31(3):

7 Onset Peak Duration Administration How supplied Dose conversion Compatibility Stability at room temperature Cost 6 hours Nosignificant peak > 24 hours Route: SubQ injection Timing: same time every day 300 units/ml. 1.5 ml disposable pen From once daily detemir: convert unit per unit and give once daily From twice daily detemir: reduce total daily dose by 20% and give once daily From U 100 glargine once daily: convert unit per unit and give once daily From U 100 glargine twice daily: convert unit per unit (or reduce by ~10% or less) and give once daily No specific information to guide switch from NPH Do not mix 28 days High; $300 for 3 pens Pharmacist's Letter 2014; 30(6): Pharmacist's Letter 2015; 31(3): Investigational Drugs Phase I Phase II Phase III Phase IV Insulin Degludec Ultra long acting basal insulin Duration ~ 40 hours Administered daily Precipitates and forms depot in the subcutaneous space and undergoes highly predictable, gradual dissociation Low peak and trough Flexible dose timing Efficacy similar to glargine but less hypoglycemia and weight gain Rejected by FDA in 2013 Resubmitted to FDA after interim analysis of ongoing DEVOTE CV outcomes study Faster Acting Insulin Aspart Bolus insulin in phase 3 trials Type 1 and type 2 A1c lowering found non inferior to insulin aspart Lower post prandial blood glucose No differences in adverse events Type 1 diabetes Significantly lower A1c levels compared with insulin aspart Phase 3 trials Tambascia and Eliaschewitz. Diabetology & Metabolic Syndrome (2015) 7:57 Insulin Peglispro Insulin lispro bound to polyethylene glycol (PEG) Hepatospecific basal insulin Compared to glargine in patients with type 2 Superior A1c reduction Greater reduction from baseline More study patients achieved A1C<7% Lower rates of nocturnal hypoglycemia Induced weight loss as opposed to weight gain AST, ALT, and triglycerides No severe drug induced liver damage Similar rates of MACE More injection site reactions Phase 3 MABp1 T2 18C3 Type 2 diabetes Therapeutic monoclonal antibody targets and neutralizes IL 1α Reduces inflammation that compromises pancreas function and glycemic control Phase 2 Diabetes 2014;63:

8 Semaglutide (OG217SC ) Long acting GLP 1 analogue OG217SC: Oral formulation Administered once daily Semaglutide SubQ formulation Administered once weekly Phase 3 Accessed 9/4/15. 8