9/29/2014 + Diabetes Update: Guidelines, Treatment Options & Trends Melissa Max, PharmD, BC-ADM, CDE Assistant Professor of Pharmacy Practice Harding University College of Pharmacy + Disclosure Conflicts Of Interest and Financial Relationships Disclosures: Melissa Max, PharmD, BC-ADM, CDE – No COI/Financial Relationships to Disclose. Learning Objectives Analyze differences between the recommendations of the ADA/EASD and the AACE regarding the treatment of diabetes. Interpret recent recommendations regarding interventions for patients with prediabetes/at increased risk for developing diabetes. Describe the place in therapy for newer pharmacotherapeutic agents. Apply knowledge of evidence-based recommendations to specific patient cases. Identify trends in pharmacotherapeutic management of diabetes. 1 9/29/2014 + Type 2 Diabetes (T2D) Overview Hallmarks of T2D Decreased insulin sensitivity Progressive loss of β cell function Therapeutic goals are not exclusively glucocentric Optimizing physical activity, weight loss and healthy eating are key Progressive disease Monotherapy failure Next steps? + Inpatient Use Insulin remains gold standard Significant concerns regarding the use of metformin, secretagogues and GLP1 RAs in inpatient setting Imperative that pharmacists be familiar with various diabetes pharmacotherapeutic agents as patients will be admitted and discharged on these therapies + Current Guidelines American Diabetes Association annual clinical practice recommendations, released each January American Diabetes Association and European Association for the Study of Diabetes 2012 Position Statement for T2D American Association of Clinical Endocrinologists Comprehensive Diabetes Management Algorithm 2013 2 9/29/2014 Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 + ADA/EASD Summary Metformin—first line Consider insulin as initial therapy if significant hyperglycemia or high A1C If noninsulin monotherapy not effective over 3 months, add a second oral agent, GLP-1 agent , or insulin Each new class of agent added lowers A1C ~1% 3 9/29/2014 + AACE & ADA/EASD Comparison AACE ADA/EASD A1C target <6.5% A1C target < 7%* Monotherapy if A1C < 7.5% May consider lifestyle alone for 3 months if Dual therapy for A1C A1C < 7.5% 7.6-9% Dual therapy if A1C ≥ Consider use of insulin as initial therapy— 9% A1C > 9% Consider use of insulin Focus on total cost of as initial therapy— therapy A1C ≥ 10% 4 9/29/2014 + Multifactorial Interventions Glucose lowering Optimal Lifestyle Lipid modification modification CV risk & tobacco reduction cessation BP lowering Goals for Glycemic Control ADA 1 AACE 2 A1C (%) <7 a ≤6.5 Fasting/preprandial 70–130 mg/dL <110 mg/dL glucose Peak postprandial <180 mg/dL <140 mg/dL b glucose aGoal for most adult patients. Goal for individual patients is A1C as close to normal (<6%) as possible without significant hypoglycemia. b2-hour postprandial. 1. ADA Position Statement 2012. Available at: http://care.diabetesjournals.org/content/35/Supplement_1/S11.full.pdf+html. 2. AACE Guidelines 2011. Available at: https://www.aace.com/sites/default/files/DMGuidelinesCCP.pdf. + Individualization of A1C Goal Tighter targets (6.0 - 6.5 %) – younger, healthier Looser targets (7.5 – 8.0 % or more) – older, comorbidities, risk of hypoglycemia Avoidance of hypoglycemia 5 9/29/2014 + Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 (Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554) + Antihyperglycemic Therapy Nonpharmacologic Weight optimization Healthy diet Increased physical activity Pharmacotherapeutic options Oral agents Parenterals Non-insulin GLP-1 RA Amylin mimetic Insulin + 12 Drug Classes Biguanides Bile Acid Sequestrants Sulfonylureas DPP-4 Inhibitors Meglitinides GLP-1 Receptor Agonists* Amylin Mimetic* Thiazolidinediones Insulin* Alpha Glucosidase Inhibitors Sodium Glucose Co- Transporter-2 (SGLT2) Dopamine-2 Agonists Inhibitors 6 9/29/2014 + Drug Selection Considerations Duration of disease Which blood glucose level is not at target Patient preference for route of administration The degree of A1C-lowering effect required to achieve goal Adverse effect profile and the patient’s tolerability Comorbidities + Primary Glucose Lowering Effect Fasting Post-prandial Metformin GLP-1 Agonists* DPP-4 Inhibitors TZD SU SU Rapid-acting insulin Long-acting insulin Alpha-glucosidase inhibitors Meglitinides Pramlintide + Weight Weight Loss/Neutral Weight Gain GLP-1 Agonists* Insulin DPP4 Inhibitors SU (neutral) TZD SGLT2 Inhibitors Metformin (neutral) Pramlintide 7 9/29/2014 + Pharmacotherapy Pearls + SU Cautions Risk of hypoglycemia is substantially increased in the elderly Even a mild episode of hypoglycemia may lead to adverse outcomes in frail elderly patients. Avoidance of hypoglycemia is an important consideration in choosing therapeutic agents and establishing glycemic goals in elderly adults. Effective dose generally about ½ maximum dose + Sulfonylureas (SU) Avoid glyburide in older adults Assess patients for hypoglycemia regularly More likely to occur: After exercise/missed meals Eat poorly or abuse alcohol Impaired renal or cardiac function Following hospitalization In patients with T2D, hypoglycemia risk is linked more to treatment strategies than A1C If recurrent/severe hypoglycemia occurs, strongly consider changing therapy and/or targets 8 9/29/2014 + Metformin Cautions Use in renal dysfunction CI: Scr> 1.5 mg/dL male, > 1.4 mg/dL female Decrease dose if GFR < 45, d/c if < 30 Other cautions Heart failure History of alcoholism/binge drinking Age > 80 years Active liver disease GI intolerance & weight loss Hypoxic conditions—lactic acidosis Iodinated contrast material + Metformin Pearls Effective treatment dose generally 1500-2000 mg daily Patient counseling GI distress in ~30%, transient Administer with meals, consider XR formulation B12 + TZD Pearls May be used in renal impairment Do not cause hypoglycemia Should not be used in patients with class III or IV HF AE: edema, fractures, bladder CA 9 9/29/2014 + Recent Approvals SGLT2 Inhibitors DPP4 Inhibitor/Combo Canagliflozin Alogliptin Dapagliflozin Alogliptin + metformin Empagliflozin Alogliptin + pioglitazone + Recent Approvals GLP1 Agonist New Indication Albiglutide Liraglutide Once weekly; SQ 3 mg daily 30 mg once weekly; FDA committee may increase to 50 mg recommendation 9/12/14 once weekly if inadequate glycemic response + SGLT2 Inhibitors Sodium-glucose co-transporter type 2 (SGLT2) Inhibitors MOA: inhibition of SGLT2 receptors in kidney responsible for glucose reabsorption in proximal tubule Action—reduce reabsorption of filtered glucose, lower the renal threshold for glucose, and increase urinary glucose excretion Insulin independent MOA; decreases fasting and post-prandial glucose concentrations 10 9/29/2014 + SGLT2 Pearls Benefit AE/Risk Weight loss Genital mycotic infections Blood pressure UTI Low incidence of Hypotension hypoglycemia Lipid effects Pleiotropic benefit Renal effects Similar to DPP4 inhibitors in A1C Bladder cancer lowering efficacy + SGLT2 Dosing & Administration Canagliflozin 100-300 mg daily dose; before the first meal of the day Moderate renal impairment [eGFR] 45 to 59 mL/min— max dose 100 mg daily Not indicated in patients with GFR <45 mL/min or in patients with severe hepatic impairment Dapagliflozin 10 mg once daily, with or without food Not recommended for use in patients with eGFR < 60 mL/min or in patients with active bladder cancer For patients with severely reduced liver function, starting dose of 5 mg is recommended + SGLT2 Dosing & Administration Empagliflozin 10 mg and 25 mg tablet CI Severe renal impairment (eGFR <30 mL/minute/1.73 m2) ESRD or dialysis Anticipated availability currently undetermined 11 9/29/2014 + SGLT2 Place in Therapy Add-on to metformin, after trying usual second-line therapies Not mentioned in the ADA guidelines, as these guidelines were published before the approval of SGLT2 inhibitors The AACE consider these agents to use with caution: as monotherapy in patients with an A1C less than 7.5%; as part of a dual or triple regimen in those with an A1C of 7.5% to 9.0%. Incretin Hormones + DPP- 4 Inhibitors MOA: prolong the t½ of GLP-1 and stimulate glucose- dependent insulin secretion, reducing postprandial glucose elevations Efficacy: decrease A1C 0.7-1% Adverse effects: Upper respiratory infections, UTI, HA Pancreatitis Low incidence of hypoglycemia Weight neutral 12 9/29/2014 + DPP-4 Inhibitors Sitagliptin Dose: 25-100 mg daily CrCl ≥50 ml/min, dose is 100 mg daily CrCl <50 but ≥ 30 ml/min, dose is 50 mg daily CrCl <30 ml/min, dose is 25 mg daily Linagliptin Dose: 5 mg daily + DPP-4 Inhibitors Saxagliptin Dose: 2.5-5 mg daily 2.5 mg dose for patients with CrCl ≤ 50 ml/min Alogliptin Dose 12.5-25 mg daily Reduce by half for patients with CrCl 30-50 ml/min + DPP- 4 Inhibitors: Place in Therapy ADA considers these as second-line therapies to be added on to metformin. AACE recommends these as one of several preferred agents, after metformin, as monotherapy. They can be used as part of a dual therapy regimen. They can be considered as part of a multi-drug regimen with metformin, in drug-naïve, asymptomatic patients with A1C > 9%. 13 9/29/2014 + GLP-1 Receptor Agonists MOA: similar to human GLP-1 Enhance insulin secretion Suppress postprandial glucagon when blood glucose elevated;