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New Medicines for Type 2 Diabetes 4

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New Medicines for Type 2 Diabetes 4 6/17/2019 1. Oral Secretagogues (e.g. sulfonylureas) 2. Metformin 3. Alpha glucosidase inhibitors New medicines for type 2 diabetes 4. Thiazolidinediones 5. GLP-1 receptor agonists 6. DPP-4 inhibitors 7. SGLT2 inhibitors 8. Insulin 9. Pramlintide 10. (Bromocriptine; colesevelam) ADA/EASD algorithm Glycemic targets 6 classes of drugs: • Younger patients with short diabetes duration HbA1c < 7% reduces risk of microvascular & macrovascular Metformin complications (aim for 6% if it can be done safely) GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone • Patients with history of severe hypoglycemia & advanced SGLT2 inhibitors atherosclerosis should not aim for < 7% Insulin metformin Metformin Metformin More complex • Elderly with limited life expectancy <8% + another + 2 others insulin regimens • Pregnancy ~ 6 % In making therapeutic decision take into account efficacy, hypoglycemia risk, effect on weight, major side effects, cost, cardiovascular & renal benefits • Children ages 0-6 <8.5% ; 6-12 <8%; 13-19 <7.5% 6/17/2019 GLP1 receptor agonists and DPP4 inhibitors GLP-1 receptor agonists GLP-1 receptor agonists : adverse events Exenatide (Byetta) 5 & 10mcg Inject twice daily. Reduce dose 5 mcg stage 3 CKD. Do not use for GFR < 30 * Placebo Exenatide (n= 483) (963) Exenatide LAR 2mg powder - Resuspend in diluent and inject SC (Bydureon) resuspend weekly Nausea 18 % 44 % Liraglutide 0.6, 1.2 and 1.8 mg Usual dose 1.2 mg daily. No dose Vomiting 4 13 (Victoza) change in renal failure Diarrhea 6 13 Albiglutide 30 mg Weekly. No dose change renal failure Feeling jittery 4 9 (Tanzeum) Dizziness 6 9 Dulaglutide 0.75, 1.5 mg Usually does 0.75 mg weekly. No dose Headache 6 9 (Trulicity) change renal failure. Dyspepsia 3 6 Lixisenatide 10, 20 mcg 20 mcg daily. No dose change eGFR (Adlyxin) >30* Semaglutide 0.25, 0.5, 1 mg 0.5 mg weekly. No dose change renal (Ozempic) failure * Exenatide and lixisenatide renal excreted. Others metabolized by proteolysis 6/17/2019 Caution using GLP-1 receptor agonists in patients Differences between the GLP1 receptor agonists with renal impairment • GI symptoms less with weekly treatment FDA: 16 cases of renal kidney impairment and 62 cases of • Weight loss greater with semaglutide compared to acute kidney injury in patients taking exenatide liraglutide, albiglutide, dulaglutide, exenatide • ~ 6% of patients on exenatide and 2.4% on lixisenatide - preexisting kidney disease develop antibodies that attenuate glycemic response. - one or more risk factors for kidney disease. - nausea, vomiting, and diarrhea - possible that these side effects caused volume depletion and renal injury. DPP 4 inhibitors DPP4 inhibitors: adverse events Sitagliptin (Januvia) 25, 50, 100 mg 100 mg daily usual dose. Use 50 mg for GFR 30-50; 25 mg for < 30 Saxagliptin (Onglyza) 2.5, 5 mg 5 mg daily usual dose. Use 2.5 mg • Nasopharyngitis; upper respiratory infections if GFR< 50 or if taking strong CYP/3A4 inhibitors Linagliptin(Tradjenta) 5 mg 5 mg daily. No dose changerenal • Allergic reactions – angioedema, anaphylaxis, failure Alogliptin (Nesina) 6.25,12.5,25 mg 25 mg daily usual dose. Use 12.5 exfoliative dermatologic reactions mg for GFR 30-60; 6.25 mg for < 30 • Joint pains that resolve with a month of stopping the drug 6/17/2019 Postmarketing study with Saxagliptin – 16, 492 T2D randomized to Saxagliptin or Placebo. Mean followup Differences between the DPP4 Inhibitors 2.1 years • Linagliptin- no dose adjustment for renal or liver disease 289, 3.5% on Saxagliptin vs 228, 2.8% on placebo admitted to hospital for heart failure (P=0.007) • Sitagliptin/saxagliptin/alogliptin adjust dose if renal disease Scirica et al Circ. 130:1579 (2014) • Adjust saxagliptin dose if a strong CYP3A4/5 inhibitor is prescribed Alogliptin 106 admission for heart failure (3.1%) vs Placebo 89 (2.9%) NS (5380 patients, median followup 18 months) Cases of pancreatitis during clinical trials with GLP-1 receptor agonists No cases of pancreatitis reported during clinical Experimental drug Comparator group trials with sitagliptin and saxagliptin. FDA adverse (placebo; other reporting mechanism 2009 – 88 cases of acute meds; insulin) 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 Albiglutide 6 2 (4311 patient yrs) & no cases in 1183 patients on Dulaglutide 5 1 placebo (433 patient yrs). Lixisenatide 21 14 Semaglutide 7 3 With alogliptin there were 11 cases in 5902 patients exposed to drug (0.2%) and 5 cases in 5183 on comparator drugs (<0.1%) 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 6/17/2019 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 if liver disease Empagliflozin (Jardiance) 10,25 mg 10 mg daily usual dose. Can use 25 for additional glucose lowering SGLT2 inhibitors Ertugliflozin (Steglatro) 5, 15 mg 5 mg daily usual dose. Can use 15 for additional glucose lowering SGLT 2 inhibitors lower threshold for glycosuria to 70 to 90 mg/dl 6/17/2019 100 mg canagliflozin lowers fasting and postprandial glucose SGLT2 inhibitors – adverse effects Genital mycotic infections; urinary tract infections ~ 8-9 % Case reports of pyelonephritis and septicemia Necrotizing fasciitis of the perineum Hypotension Amputation (canagliflozin) Bladder cancer and breast cancer (dapagliflozin) in clinical trials Diabetic ketoacidosis if used in Type 1 diabetes patients or patients labeled as having type 2 diabetes but who are very insulin deficient and ketosis prone Differences between the SGLT2 inhibitors • Inducers of glucuronosyl transferase 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 Insulins • Dapagliflozin & ertugliflozin- do no use if eGFR < 60 6/17/2019 Effective Insulin Preparations Onset of Action Peak Action Duration 4 T study - 708 T2D on metformin and/or sulfonylurea Insulins lispro, 5–15 minutes 1–1.5 hours 3–4 hours aspart, glulisine add Human regular 30–60 minutes 2 hours 6–8 hours 5-15 minutes 1 hour 3 hours Inhaled regular insulin Human NPH 2–4 hours 6–7 hours 10–20 hours Twice daily Insulin aspart Insulin detemir Insulin glargine 0.5 -1 hour Flat ~24 hours Novolog Mix 70/30 premeals Insulin detemir 0.5 - 1 hour Flat 17 hours Insulin degludec 0.5-1.5 hours Flat > 42 hours Used predetermined insulin titration algorithm Fiasp – insulin aspart formulated with niacinamide ~ 10 minutes faster onset of action; and lower postprandial peak at 1 hour Holman et al N Engl J Med 357:1716 (2008) At 1 year: Novolog Mix and Novolog equal glucose lowering; detemir less (p<0.001) -but greater wt.gain & hypoglycemia Clinical approach 6/17/2019 Decisions based on: ADA/EASD algorithm Efficacy – DPP4 and SGLT2 inhibitors moderate; others high 6 classes of drugs: Hypoglycemia risk – oral secretagogues and insulin have high risk Metformin Effect on weight – metformin, DPP4 neutral; GLP1 receptor agonists, SGLT2 GLP1 receptor agonists/DPP 4 inhibitors inhibitors promote weight loss; oral secretagogues, insulin, Sulfonylureas (+other secretagogues) pioglitazone cause weight gain Pioglitazone SGLT2 inhibitors Major side effects - metformin: lactic acidosis Insulin pioglitazone: fractures; fluid retention, possib. bladder CA GLP1 receptor agonists: nausea, vomiting, possibly pancreatitis metformin Metformin Metformin More complex DPP4 inhibitors: may cause pancreatitis, joint pains + another + 2 others insulin regimens 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, cardiovascular & renal benefits CVS benefit – Metformin, GLP1 receptor agonists, SGLT2 inhibitors Renal benefit – SGLT2 inhibitors , possibly pioglitazone Randomized controlled study of gastric banding vs lifestyle weight loss in 60 obese patients (BMI 30 to 40) with DM < 2 years Weight loss Dixon et al. JAMA 299: 316 (2008) 6/17/2019 Effect of exenatide therapy for 30 wks on glycemic control and Exenatide promotes weight loss when added to weight loss in metformin treated type 2 patients diet and exercise in obese nondiabetic subjects 0 0.2 0 -1 0.1 -0.5 0 -2 -0.1 -1 Total (73) -0.2 -3 Placebo Nausea (18) -0.3 -1.5 5 mcg No Nausea (55) -0.4 10 mcg Kg -4 -0.5 -2 -0.6 -5 -0.7 -2.5 -0.8 -6 -0.9 -3 Exenatide Placebo Weight loss (kg) Rosenstock et al. Diabetes Care 33: 1173 (2010) % HbA1c lowering * Liraglutide 3 mg daily approved for weight loss DeFronzo et al. Diabetes 28:1092; 2005 Weight loss Metformin Neutralor <1 kg * GLP1 receptor agonists 1.5 to 4 kg ** SGLT2 inhibitors 2 to 5 kg * Metformin ameliorates wt gain with sulfonylureas, thiazolidinediones, insulin Cardiovascular benefit and augments wt. loss with GLP1 receptor agonists **Semaglutide > liraglutide, exenatide> lixisenatide, dulaglutide > albiglutide Madsbad Diab Obes Metab 2016, 18:317 6/17/2019 2008 – FDA required manufacturers to perform a long term cardiovascular outcome trial for safety • Metformin (UKPDS) • Pioglitazone • GLP1 receptor agonists • Trials were designed to rule out unacceptable CV risk • SGLT2 inhibitors • Performed in patients with established CVD or high risk for CVD • Primary outcome = 3 point major adverse cardiovascular events (MACE) – CV death, nonfatal MI, nonfatal stroke ( + admission for unstable angina = 4 point MACE) • Designed to minimize glycemic differences between Rx and placebo arms – so Rx intensification in placebo arm. In most trials, Rx arm had better HbA1c • High proportion of patients on antihypertensives, lipid lowering and antiplatelet Rx Metformin as the first line therapy for overweight type 2 DM 5238 DM with with CVS disease (MI, CAD, PVD or stroke).
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