6/22/2015. New medicines for type 2 diabetes when do you use them

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1 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) 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: classes of drugs: ADA/EASD algorithm 2015 Metformin GLP1 receptor agonists/dpp 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin metformin Metformin + another Metformin + 2 others More complex insulin regimens In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost 1

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

3 DPP 4 inhibitors Sitagliptin (Januvia) (2006) Saxagliptin (Onglyza) (2009) Linagliptin (Tradjenta) (2011) Alogliptin (Nesina) (2013) 25, 50, 100 mg 100 mg daily usual dose. Use 50 mg for GFR 30-50; 25 mg for < , 5 mg 5 mg daily usual dose. Use 2.5 mg if GFR< 50 or if taking strong CYP/3A4 inhibitors 5 mg 5 mg daily 6.25,12.5,25 mg 25 mg daily usual dose. Use 12.5 mg for GFR 30-60; 6.25 mg for < 30 SGLT2 inhibitors Canagliflozin (Invokana) (2013) Dapagliflozin (Farxiga) (2014) Empagliflozin (Jardiance) (2014) 100 mg, 300 mg 100 mg daily usual dose. Can use 300 for additional glucose lowering 5, 10 mg 10 mg daily usual dose. Use 5 mg if liver disease 10,25 mg 10 mg daily usual dose. Can use 25 for additional glucose lowering Insulins U300 insulin glargine (Toujeo) (2015) 1.5 ml Pen Duration of action at least 24 hrs Technosphere insulin (Afrezza) (2014) 4 and 8 unit cartridges Peak levels in 12 to 15 minutes; duration 3 hours GLP1 receptor agonists and DPP4 inhibitors 3

4 Effect of exenatide therapy for 30 wks on glycemic control and weight loss in metformin treated type 2 patients Placebo 5 mcg 10 mcg % HbA1c lowering Weight loss (kg) DeFronzo et al. Diabetes 28:1092; 2005 Exenatide promotes weight loss when added to diet and exercise in obese nondiabetic subjects Kg Total (73) Nausea (18) No Nausea (55) -6 Exenatide Placebo Rosenstock et al. Diabetes Care 33: 1173 (2010) * Liraglutide 3 mg daily approved for weight loss 4

5 GLP-1 receptor agonists : adverse events HbA1c lowering with monotherapy GLP-1 receptor agonists DPP-4 inhibitors 0.5 to 1.5 % 0.4 to 0.8% Weight Decreased Neutral 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 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 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. Nasopharyngitis; upper respiratory infections Allergic reactions angioedema, anaphylaxis, exfoliative dermatologic reactions 5

6 Cases of pancreatitis during clinical trials with GLP-1 receptor agonists Experimental drug Exenatide 8 2 Liraglutide 13 1 Albiglutide 6 2 Dulaglutide 5 1 Comparator group (placebo; other meds; insulin) vs 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 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%) Used 10ug of exenatide in rats ~ 70 times the clinical dose for 75 days * Pancreatic acinar inflammation and pyknosis Cellular plasticity within the pancreas the potential for fully differentiated cells to change fate The rats had 30% reduction in weight Acinar injury Pancreatic adenocarcinoma 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 ** Acinar cells Dedifferentiated cells Endocrine cells *Nachnani et al. Diabetologia 53: 153 (2010) **Matveyenko et al. Diabetes 58: 1604 (2009) Puri & Hebrok Dev Cell 18:342 (2010) 6

7 Differences between the GLP1 receptor agonists Rats given GLP1 receptor agonists developed C- cell tumors Avoid if family or personal history of MTC; MEN 2 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 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) 7

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

9 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 < 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

10 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 Fumaryl diketopiperazine is an excipient that forms 2-2.5µm crystal (technosphere particle) that provide a large surface area for adsorption of regular insulin Insulin levels after inhaled insulin vs SC insulin analog Angelo et al J Diab Sci Tech 3:545 (2009) 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) 10

11 Technosphere insulin - Afrezza In clinical trials, inhaled insulin boluses + SC basal insulin as effective as SC insulin analogs + SC basal insulin (or a little worse) Inhaled insulin use was associated with less symptomatic & severe hypoglycemia (e.g. severe events 8.05 vs per 100 subject-months in T1D) 4 unit cartridge 0.35 mg insulin ~ 39% of dose distributed to lungs; t ½ clearance from lung epithelium ~ 1hr [1 unit SC insulin ~0.04 mg insulin] From: Sanofi Afrezza prescribing insert FDA briefing document ~ 40 ml decline in FEV1 in first 3 months which persisted for 2 years of follow-up Cough most common side effect (~27%) Bronchospasm in patients with asthma, COPD Not recommended for active smokers or recent ex-smokers Spirometry before prescribing, at 6 months and then annually FDA briefing document 11

12 Lung cancer and inhaled insulin Exubera clinical trial data * FUSE (followup study of exubera trial subjects ) 2536 subjects (34%) ** Technosphere insulin *** Inhaled insulin Comparator 6/4740 patients 1/4292 patients 18 primary lung cancers (6 deaths) 5 primary lung cancers (2 deaths) 2/2750 patient yrs 0/2169 patient yrs * All in previous cigarette smokers ** Primary lung cancer rates with Exubera 1.07/1000 patient years; Comparator 0.29/1000 patient years *** both ex smokers; and 2 cases of squamous cell lung cancers in nonsmokers after completion of trials Clinical cases ADA/EASD algorithm 2015 Decisions based on 6 classes of drugs: Metformin GLP1 receptor agonists/dpp 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin metformin Metformin + another Metformin + 2 others More complex insulin regimens Efficacy DPP4 moderate; others high Hypoglycemia risk oral secretagogues and insulin have high risk Effect on weight metformin, DPP4 neutral; GLP1 receptor agonists, SGLT2 inhibitors promote weight loss; oral secretagogues, insulin, pioglitazone cause weight gain Major side effects metformin lactic acidosis pioglitazone fractures; fluid retention, possib. bladder CA GLP1 receptor agonists nausea, vomiting, possibly pancreatitis DPP4 may cause pancreatitis SGLT inhibitors UTI; genital mycotic infections; dehydration Cost all except metformin and oral secretagogues are expensive In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost 12

13 Randomized controlled study of gastric banding vs lifestyle weight loss in 60 obese patients (BMI 30 to 40) with DM < 2 years Dixon et al. JAMA 299: 316 (2008) Case 1 UCSF yr old Caucasian man with DM 10 yrs. BMI 39.5 (290lb). On metformin for 5yrs. Stopped and on insulin. 50 units of glargine; 20 to 30 units insulin aspart premeals (total insulin ~ 125 units daily). Peripheral neuropathy; nephropathy with urine albumin 3.1 g/g creatinine. Normal creatinine. HbA1c 8.1 % Started metformin + 40 insulin glargine; 15 to 20 insulin aspart premeals. HbA1c ~ 6.7%. Weight loss ~ 4 lbs. Exenatide initiated 6 months ago I month ago taking 60 units of insulin a day; exenatide 10 mcg twice a day; Metformin XR 1000 daily. HbA1c 6.2 %. Weight 280 lbs. Urine albumin 1.4 g/g creatinine Suggested stop insulin and start glimepiride Case 2 UCSF yr old Caucasian man with DM since his late 40s. Oral agents until age 60 when placed on insulin pump. Has proliferative retinopathy; peripheral neuropathy with toe amputation; PVD with fem-pop bypass; MI history; left nephrectomy for renal CA creatinine 2.0. Admitted to UCSF with MRSA bacteremia with septic shock; epidural abscess. Patient before acute illness weighed 220 lbs after hospitalization weighed 175 lbs. Excellent control on insulin HbA1c 7.1% Oct regained weight 218 lbs; quite sedentary. HbA1c 10%. Creat 1.78 Negative antibodies for type 1 diabetes. Quite insulin resistant. Started sitagliptin 25 mg daily Jan 2015 HbA1c 8.9%. Add glipizide 5 mg BID April 2015 HbA1c 8 % 13

14 Case 3 Case 4 54 yr old Caucasian man with DM for 10 years. No complications. BMI 27.5 On metformin, glimepiride, insulin detemir (40 Units). Intolerant of GLP-1 receptor agonists. HbA1c 7.7% Started on Canagliflozin 300 mg daily 2 months later BG low 100 s; HbA1c 6.7 %; insulin detemir dose reduced. No polyuria. No infections 84 year old woman with DM for 12 yrs. BMI 41 On metformin 1000 bid, glimepiride 4 mg/day HbA1c 8.5 %. Fingerstix glucose high 100 s to low 200 s Would prefer pills to injections Canagliflozin 100 mg daily 1 week later called complain of vulvar itching and rash Canagliflozin stopped; yeast infection treated A cautionary case: SGLT2 inhibitor use in type 1 diabetes A case of needle phobia 23 year old Caucasian woman with T1D since age 8 on injections HbA1c around 8 % Started on Canagliflozin Sept 2014 Glucose levels dropped and so insulin doses were gradually decreased Insulin glargine dose reduced 30 to 10 to 8 to 2; also significant decrease in bolus insulin doses Admitted to hospital with nausea, vomiting, dehydration and ketoacidosis Diabetes clinic yr old Vietnamese woman with diabetes since age 37. BMI 18. Initially treated as type 2 diabetes. HbA1c 8-12 GAD antibody +ve Refused to inject insulin even though she agreed that the needles were almost painless (refused to use syringes or pens) 14

15 Given Novofine autocover needles Stacking can be an issue for T1D patients who are on pumps and sensors and inhaled insulin would reduce the risk of hypoglycemia Now on basal bolus insulin regimen (4 injections a day) HbA1c 6.9 to 7.4 % Dulaglutide pen you cannot see the needle Wolpert Diab Care 2008 Costs for 1 month supply (standard doses; Walgreens, Costco) Make your own toolkit Metformin (4 ); glipizide (5); repaglinide (50) Pioglitazone (12) Acarbose (48) DPP4 inhibitors ( ~ 330 ) SGLT2 inhibitors ( ~ 370) GLP1 receptor agonists (~500) Analog insulins ( ~ 400) Old insulins ( ~ 150) Metformin Oral secretagogues glipizide, glimepiride, nateglinide, repaglinide DPP4 inhibitors sitagliptin GLP-1 receptor agonists exenatide, liraglutide Insulins glargine U100, aspart, lispro, some premixed; NPH, Regular ( an SGLT2 inhibitor in the future?) 15