New medicines for type 2 diabetes when do you use them 1. Oral - PDF document

5/22/2015 New medicines for type 2 diabetes – when do you use them 1. Oral Secretagogues (e.g. sulfonylureas) 2. Metformin 3. Alpha glucosidase inhibitors 4. Thiazolidinediones 5. GLP-1 receptor agonists 6. DPP-4 inhibitors 7. Pramlintide 8. SGLT2 inhibitors 9. Insulin 10. (Bromocriptine; colesevelam) 1

5/22/2015 Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered Approach Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes Inzucchi et al. Diabetes Care 2015;38:140 – 149 ADA/EASD algorithm 2015 6 classes of drugs: Metformin GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin metformin Metformin Metformin More complex + another + 2 others insulin regimens In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost 2

5/22/2015 Glycemic targets • Younger patients with short duration of diabetes - aiming for an HbA1c of < 7% will reduce the risk of both microvascular and macrovascular complications (aim for 6% if it can be done safely) • T2D patients who can easily achieve an HbA1c of < 7% with lifestyle +/- pharmacotherapy do not need to “raise” their HbA1c • Patients with history of severe hypoglycemia & advanced atherosclerosis should not aim for < 7% 3

5/22/2015 • Children ages 0-6 <8.5% 6-12 <8% 13-19 <7.5% • Elderly with limited life expectancy <8% • Pregnancy 6 % (NICE <6.1%) GLP-1 receptor agonists Exenatide (Byetta) Pens – 5 & 10mcg Inject SC twice daily. Do not use (2005) for GFR < 30 Exenatide LAR 2mg powder Resuspend in diluent and inject (Bydureon) SC weekly Liraglutide (Victoza) Pen – 0.6, 1.2 and 1.8 Usually 1.2 mg SC daily (2010) mg Albiglutide Pen - 30 mg Inject SC weekly (Tanzeum) (2014) Dulaglutide Pen – 0.75, 1.5 mg Usually inject 0.75 mg SC (Trulicity) weekly (2014) 4

5/22/2015 DPP 4 inhibitors Sitagliptin (Januvia) 25, 50, 100 mg 100 mg daily usual dose. Use 50 (2006) mg for GFR 30-50; 25 mg for < 30 Saxagliptin (Onglyza) 2.5, 5 mg 5 mg daily usual dose. Use 2.5 mg (2009) if GFR< 50 or if taking strong CYP/3A4 inhibitors Linagliptin (Tradjenta) 5 mg 5 mg daily (2011) Alogliptin (Nesina) 6.25,12.5,25 mg 25 mg daily usual dose. Use 12.5 (2013) mg for GFR 30-60; 6.25 mg for < 30 SGLT2 inhibitors Canagliflozin (Invokana) 100 mg, 300 mg 100 mg daily usual dose. Can use (2013) 300 for additional glucose lowering Dapagliflozin (Farxiga) 5, 10 mg 10 mg daily usual dose. Use 5 mg (2014) if liver disease Empagliflozin 10,25 mg 10 mg daily usual dose. Can use (Jardiance) 25 for additional glucose lowering (2014) 5

5/22/2015 Insulins U300 insulin glargine 1.5 ml Pen Duration of action at least 24 hrs (Toujeo) (2015) Technosphere insulin 4 and 8 unit Peak levels in 12 to 15 minutes; (Afrezza) cartridges duration 3 hours (2014) GLP1 receptor agonists and DPP4 inhibitors 6

5/22/2015 Effect of exenatide therapy for 30 wks on glycemic control and weight loss in metformin treated type 2 patients 0 0.2 0.1 -0.5 0 -0.1 -1 -0.2 Placebo -0.3 -1.5 5 mcg -0.4 10 mcg -0.5 -2 -0.6 -0.7 -2.5 -0.8 -3 -0.9 Weight loss (kg) % HbA1c lowering DeFronzo et al. Diabetes 28:1092; 2005 7

5/22/2015 Exenatide promotes weight loss when added to diet and exercise in obese nondiabetic subjects 0 -1 -2 Total (73) -3 Nausea (18) No Nausea (55) -4 Kg -5 -6 Exenatide Placebo Rosenstock et al. Diabetes Care 33: 1173 ( 2010 ) * Liraglutide 3 mg daily approved for weight loss 8

5/22/2015 GLP-1 DPP-4 receptor inhibitors agonists HbA1c 0.5 to 1.5 % 0.4 to 0.8% lowering with monotherapy Weight Decreased Neutral These drugs have glucose dependent insulin release and have low risk for hypoglycemia GLP-1 receptor agonists : adverse events Placebo Exenatide (n= 483) (963) Nausea 18 % 44 % Vomiting 4 13 Diarrhea 6 13 Feeling jittery 4 9 Dizziness 6 9 Headache 6 9 Dyspepsia 3 6 Hypoglycemia risk increased if on sulfonylurea 9

5/22/2015 Caution using GLP-1 receptor agonists in patients with renal impairment FDA: 16 cases of renal kidney impairment and 62 cases of acute kidney injury in patients taking exenatide - preexisting kidney disease - one or more risk factors for kidney disease. - nausea, vomiting, and diarrhea - possible that these side effects caused volume depletion and renal injury. DPP4 inhibitors: adverse events • Nasopharyngitis; upper respiratory infections • Allergic reactions – angioedema, anaphylaxis, exfoliative dermatologic reactions 10

5/22/2015 Cases of pancreatitis during clinical trials with GLP-1 receptor agonists Experimental Comparator drug group (placebo; other meds; insulin) Exenatide 8 2 Liraglutide 13 1 Albiglutide 6 2 Dulaglutide 5 1 1.4-2.2 vs 0.6-0.9 cases of pancreatitis per 1000 patient years FDA reporting mechanism 30 cases of acute pancreatitis with exenatide No cases of pancreatitis reported during clinical trials with sitagliptin and saxagliptin. FDA adverse reporting mechanism 2009 – 88 cases of acute pancreatitis in patients on sitagliptin In one study with linagliptin, 8 cases of pancreatitis in 4687 patients exposed to drug (4311 patient yrs) & no cases in 1183 patients on placebo (433 patient yrs). With alogliptin there were 11 cases in 5902 patients exposed to drug (0.2%) and 5 cases in 5183 on comparator drugs (<0.1%) 11

5/22/2015 Used 10ug of exenatide in rats ~ 70 times the clinical dose for 75 days * Pancreatic acinar inflammation and pyknosis The rats had 30% reduction in weight In human islet amyloid polypeptide transgenic rats, sitagliptin (200 mg/kg ~ 140 times clinical dose) increased pancreatic ductal turnover, metaplasia and induced pancreatitis in one rat ** *Nachnani et al. Diabetologia 53: 153 (2010) ** Matveyenko et al. Diabetes 58: 1604 (2009) Cellular plasticity within the pancreas – the potential for fully differentiated cells to change fate Pancreatic Acinar injury adenocarcinoma Acinar Dedifferentiated cells cells Endocrine cells Puri & Hebrok Dev Cell 18:342 (2010) 12

5/22/2015 Rats given GLP1 receptor agonists developed C- cell tumors Avoid if family or personal history of MTC; MEN 2 Differences between the GLP1 receptor agonists • GI symptoms less with weekly treatment • Weight loss slightly greater with liraglutide • ~ 6% of patients on exenatide develop antibodies that attenuate glycemic response • Albiglutide has less weight loss than exenatide and liraglutide 13

5/22/2015 Differences between the DPP4 Inhibitors • Linagliptin- no dose adjustment for renal or liver disease • Sitagliptin/saxagliptin/alogliptin adjust dose if renal disease • Adjust saxgliptin dose if a strong CYP3A4/5 inhibitor is prescribed Postmarketing study with Saxagliptin – 16, 492 T2D randomized to Saxagliptin or Placebo. Mean followup 2.1 years 289, 3.5% on Saxagliptin vs 228, 2.8% on placebo admitted to hospital for heart failure (P=0.007 ) Scirica et al Circ. 130:1579 (2014) Alogliptin 106 admission for heart failu (3.1%) vs Placebo 89 (2.9%) NS (5380 patients, median followup 18 months) 14

5/22/2015 SGLT2 inhibitors 15

5/22/2015 SGLT 2 inhibitors lower threshold for glycosuria to 70 to 90 mg/dl 100 mg canagliflozin lowers fasting and postprandial glucose 16

5/22/2015 Canagliflozin (Invokana ) Reduces threshold for glycosuria to 70 to 90 mg/dl Improves fasting and postprandial glucose levels Lowers HbA1c by 0.6 to 1 % Give 100 mg daily and if necessary 300 mg daily Weight lost ~ 5 to 10lbs; decreases systolic BP; raises HDL and LDL chol Side effects – Vaginal yeast infection (~10.4%); UTI (~ 6%); dehydration Do not use if GFR < 45 mL/min; lower dose if < 60 mL/min Differences between the SGLT2 inhibitors • Inducers of UDP-glucuronosyltransferase enzymes (e.g. rifampin, phenytoin, phenobarbital, ritonavir) increase metabolism of canagliflozin • Dapagliflozin- higher rates of breast cancer and bladder cancer in clinical trials • Canaglifozin & empagliflozin – do not use if eGFR < 45 • Dapagliflozin- do no use if eGFR < 60 17

5/22/2015 Insulins 36 hr euglycemic clamp in T1D patients after 8 days of daily injections of insulin glargine – U100 or U300 Becker et al. Diabetes Care 38: 637 (2015) 18

5/22/2015 T1D – 0.2 units/Kg (from FDA.gov) Results from open label clinical trials with U300 insulin glargine In the two type 1 studies – control was the same and no difference in overall hypoglycemia rates In the six type 2 studies – control was the same; 2 of 6 studies had less hypoglycemia (glucose 70 or less; or needed help to treat low) Higher doses of U300 were required compared to U100 to achieve glycemic targets (~ 11 to 18% more insulin units) Rosselli et al J Pharm Tech 2015 19

5/22/2015 Fumaryl diketopiperazine is an excipient that forms 2-2.5µm crystal (technosphere particle) that provide a large surface area for adsorption of regular insulin Angelo et al J Diab Sci Tech 3:545 (2009) Insulin levels after inhaled insulin vs SC insulin analog Time to maximal glucose infusion rate : 53 mins inhaled insulin; 108 mins SC analog (back to baseline 3 hr with inhaled insulin; 4 hr with SC analog) 20