6/22/2015 1. Oral Secretagogues (e.g. sulfonylureas) 2. Metformin - PowerPoint PPT Presentation

6/22/2015 1. Oral Secretagogues (e.g. sulfonylureas) 2. Metformin 3. Alpha glucosidase inhibitors 4. Thiazolidinediones New medicines for type 2 diabetes 5. GLP-1 receptor agonists – when do you use them 6. DPP-4 inhibitors 7. Pramlintide 8. SGLT2 inhibitors 9. Insulin 10. (Bromocriptine; colesevelam) ADA/EASD algorithm 2015 Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered Approach 6 classes of drugs: Metformin Update to a Position Statement of the American Diabetes GLP1 receptor agonists/DPP 4 inhibitors Association and the European Association for the Study of Diabetes Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Inzucchi et al. Diabetes Care 2015;38:140–149 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 1

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

6/22/2015 DPP 4 inhibitors SGLT2 inhibitors Sitagliptin (Januvia) 25, 50, 100 mg 100 mg daily usual dose. Use 50 Canagliflozin (Invokana) 100 mg, 300 mg 100 mg daily usual dose. Can use (2006) mg for GFR 30-50; 25 mg for < 30 (2013) 300 for additional glucose lowering Saxagliptin (Onglyza) 2.5, 5 mg 5 mg daily usual dose. Use 2.5 mg (2009) if GFR< 50 or if taking strong Dapagliflozin (Farxiga) 5, 10 mg 10 mg daily usual dose. Use 5 mg CYP/3A4 inhibitors (2014) if liver disease Linagliptin (Tradjenta) 5 mg 5 mg daily Empagliflozin 10,25 mg 10 mg daily usual dose. Can use (2011) (Jardiance) 25 for additional glucose lowering (2014) 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 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 3

6/22/2015 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 -2.5 -0.7 -0.8 -3 -0.9 Weight loss (kg) % HbA1c lowering DeFronzo et al. Diabetes 28:1092; 2005 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 4

6/22/2015 GLP-1 receptor agonists : adverse events GLP-1 DPP-4 Placebo Exenatide receptor inhibitors (n= 483) (963) agonists Nausea 18 % 44 % HbA1c 0.5 to 1.5 % 0.4 to 0.8% Vomiting 4 13 lowering with Diarrhea 6 13 monotherapy Feeling jittery 4 9 Dizziness 6 9 Weight Decreased Neutral Headache 6 9 Dyspepsia 3 6 Hypoglycemia risk increased if on sulfonylurea These drugs have glucose dependent insulin release and have low risk for hypoglycemia Caution using GLP-1 receptor agonists in patients with renal impairment DPP4 inhibitors: adverse events FDA: 16 cases of renal kidney impairment and 62 cases of • Nasopharyngitis; upper respiratory infections acute kidney injury in patients taking exenatide • Allergic reactions – angioedema, anaphylaxis, - preexisting kidney disease exfoliative dermatologic reactions - one or more risk factors for kidney disease. - nausea, vomiting, and diarrhea - possible that these side effects caused volume depletion and renal injury. 5

6/22/2015 Cases of pancreatitis during clinical trials with GLP-1 receptor agonists No cases of pancreatitis reported during clinical trials with sitagliptin and saxagliptin. Experimental Comparator drug group (placebo; other meds; FDA adverse reporting mechanism 2009 – 88 cases insulin) of acute pancreatitis in patients on sitagliptin Exenatide 8 2 In one study with linagliptin, 8 cases of Liraglutide 13 1 pancreatitis in 4687 patients exposed to drug (4311 patient yrs) & no cases in 1183 patients on Albiglutide 6 2 placebo (433 patient yrs). Dulaglutide 5 1 With alogliptin there were 11 cases in 5902 patients exposed to drug (0.2%) and 5 cases in 1.4-2.2 vs 0.6-0.9 cases of pancreatitis per 1000 patient years 5183 on comparator drugs (<0.1%) FDA reporting mechanism 30 cases of acute pancreatitis with exenatide Cellular plasticity within the pancreas – the potential for fully Used 10ug of exenatide in rats ~ 70 times the differentiated cells to change fate clinical dose for 75 days * Pancreatic acinar inflammation and pyknosis Acinar Pancreatic The rats had 30% reduction in weight injury adenocarcinoma Acinar Dedifferentiated cells cells In human islet amyloid polypeptide transgenic rats, sitagliptin (200 mg/kg ~ 140 times clinical dose) increased pancreatic ductal turnover, Endocrine cells metaplasia and induced pancreatitis in one rat ** *Nachnani et al. Diabetologia 53: 153 (2010) Puri & Hebrok Dev Cell 18:342 (2010) ** Matveyenko et al. Diabetes 58: 1604 (2009) 6

6/22/2015 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 Rats given GLP1 receptor agonists developed C- cell tumors attenuate glycemic response • Albiglutide has less weight loss than exenatide and Avoid if family or personal history of MTC; MEN 2 liraglutide Postmarketing study with Saxagliptin – 16, 492 T2D Differences between the DPP4 Inhibitors randomized to Saxagliptin or Placebo. Mean followup 2.1 years • Linagliptin- no dose adjustment for renal or liver disease 289, 3.5% on Saxagliptin vs 228, 2.8% on placebo • Sitagliptin/saxagliptin/alogliptin adjust dose if renal disease admitted to hospital for heart failure (P=0.007 ) Scirica et al Circ. 130:1579 (2014) • Adjust saxgliptin dose if a strong CYP3A4/5 inhibitor is prescribed Alogliptin 106 admission for heart failu (3.1%) vs Placebo 89 (2.9%) NS (5380 patients, median followup 18 months) 7

6/22/2015 SGLT2 inhibitors SGLT 2 inhibitors lower threshold for glycosuria to 70 to 90 mg/dl 100 mg canagliflozin lowers fasting and postprandial glucose 8

6/22/2015 Differences between the SGLT2 inhibitors Canagliflozin (Invokana ) • Inducers of UDP-glucuronosyltransferase enzymes (e.g. rifampin, Reduces threshold for glycosuria to 70 to 90 mg/dl phenytoin, phenobarbital, ritonavir) increase metabolism of Improves fasting and postprandial glucose levels canagliflozin • Dapagliflozin- higher rates of breast cancer and bladder cancer in Lowers HbA1c by 0.6 to 1 % clinical trials Give 100 mg daily and if necessary 300 mg daily • Canaglifozin & empagliflozin – do not use if eGFR < 45 • Dapagliflozin- do no use if eGFR < 60 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 36 hr euglycemic clamp in T1D patients after 8 days of daily injections of insulin glargine – U100 or U300 Insulins Becker et al. Diabetes Care 38: 637 (2015) 9

6/22/2015 Results from open label clinical trials with U300 insulin glargine T1D – 0.2 units/Kg (from FDA.gov) 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 Fumaryl diketopiperazine is an excipient that forms 2-2.5µm crystal (technosphere Insulin levels after inhaled insulin vs SC insulin analog particle) that provide a large surface area for adsorption of regular insulin 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) Angelo et al J Diab Sci Tech 3:545 (2009) 10