Effective and Timely Management of Patients with T2DM: A Case-based Approach

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1 Educational Objectives Effective and Timely Management of Patients with T2DM: A Case-based Approach M. Susan Burke, MD, FACP Clinical Associate Professor of Medicine Sidney Kimmel Medical College at Thomas Jefferson University Senior Advisor, Lankenau Medical Associates Lankenau Medical Center Wynnewood, PA Ellen H. Miller, MD Professor of Science Education & Medicine Hofstra Northwell School of Medicine Senior Medical Director North Shore - LIJ CareConnect East Hills, NY At the conclusion of this activity, participants should be able to demonstrate the ability to: Assess the current understanding of the pathophysiology of T2DM and the targets of various anti-hyperglycemic therapies Target the pathophysiological disturbances in patients with T2DM using mono- or combination therapies based on their efficacy and safety Manage patients with T2DM optimally in accordance with the guideline recommendations Achieve optimal glycemic control in a timely manner in patients with T2DM who are not at goal by initiating and intensifying insulin or insulin plus non-insulin therapies appropriately Communicate effectively with patients with T2DM to overcome barriers, minimize risk, and improve adherence New Thinking and Approaches in the Management of Type 2 Diabetes Diabetes and the National Quality Strategy Diabetes Prevalence in the US, 2012 National Diabetes Statistics Report, 2014 Obesity and T2D: A Common Burden Obesity Prevalence Among US Adults, 2013 County-level Estimates of Diagnosed T2D Among US Adults, 2011 Statistics shown are for all ages CDC. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States. Atlanta, GA: US Department of Health and Human Services, Obesity = BMI 30 kg/m 2 or ~30 lbs. overweight for 5 4 person CDC Behavioral Risk Factor Surveillance Systems; CDC Diabetes Public Health Resource Center. 1

2 Approach to the Management of Hyperglycemia ADA: Foundations of Care Patient/Disease Features Risks associated with hypoglycemia & other drug adverse effects Disease Duration Life expectancy Important comorbidities Established vascular complications Patient attitude & expected treatment efforts more A1C less stringent 7% stringent low high newly diagnosed long-standing long short absent few/mild severe absent few/mild severe Self-management Education Nutrition Promote healthful eating patterns, appropriate portion sizes; address personal and cultural preferences Achieve and maintain body weight goals and individualized glycemic, blood pressure, and lipid goals Physical Activity Adults with diabetes: at least 150 min/wk of moderate-intensity aerobic activity over at least 3 days/week; resistance training at least twice weekly Smoking Cessation Resources & support system highly motivated, adherent, excellent self-care capabilities readily available less motivated, nonadherent, poor self-care capabilities limited Advise all patients not to use cigarettes, other tobacco products, or e-cigarettes; diabetes care should include routine smoking cessation counseling American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care. 2016;39 (Suppl 1):S39-S46 Adapted from American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care. 2016;39(Suppl 1):S60-S71. ADA: Foundations of Care Immunizations in Diabetes Vaccine frequency of administration Influenza annually PPSV23, 1 injection before age 65 PVC13 plus PPSV23, 1 injection each, in series 1 year apart Hepatitis B, 3 injection series Td (or Tdap), every 10 years Zoster vaccine Patient age 6 months years 65 years years consider in 60 years 19 years 60 years Adapted from American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care. 2016;39(Suppl 1):S60-S71. Diabetes Mellitus: A Constellation of Complications Peripheral Vascular Disease Gastropathy Dyslipidemia Erectile Dysfunction Renal Disease Diabetes Cardiovascular Disease Peripheral Neuropathy Hypertension Retinopathy/ Macular Edema Autonomic Neuropathy Looking Beyond Glucose Control Screening Recommendations BP Targets People with T2DM and hypertension should be treated to a systolic blood pressure goal of <140 mmhg; lower targets may be appropriate for certain individuals Consider aspirin therapy ( mg/day) As a primary prevention strategy in those at increased cardiovascular risk (10-year risk >10%) Includes most men or women with DM age 50 years who have 1 major risk factor Remember to use moderate or high dose statins in most diabetics >40, depending on risk Nephropathy At least yearly, assess urine albumin excretion and estimated glomerular filtration rate (egfr) Retinopathy Dilated exam by ophthalmologist at diagnosis and Q 1-2 years Regular foot care Neuropathy, including monofilament testing At time of diagnosis and annually Adapted from American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care. 2016;39(Suppl 1):S60-S71. 2

3 NQS Priorities Mandated by the Patient Protection and Affordable Care Act, the National Quality Strategy (NQS) was developed to improve patient health and health care quality. The NQS priorities address the most common health concerns among patients: 1. Patient safety 2. Engaging patients and caregivers 3. Coordinating patient care 4. Disseminating effective prevention and treatment practices for leading causes of mortality 5. Promoting use of best practices to enable healthy living within communities 6. Developing new health care delivery models to provide affordable quality care for individuals, families, employers, and governments CMS National Quality Measures in Diabetes Diabetes: Hemoglobin A1C Poor Control Diabetes: Low Density Lipoprotein (LDL-C) Control (<100 mg/dl) Diabetic Retinopathy: Documentation of Presence or Absence of Macular Edema and Level of Severity of Retinopathy Diabetic Retinopathy: Communication with the Physician Managing Ongoing Diabetes Care Diabetes: Medical Attention for Nephropathy Diabetes Mellitus: Diabetic Foot and Ankle Care, Peripheral Neuropathy Neurological Evaluation Diabetes Mellitus: Diabetic Foot and Ankle Care, Ulcer Prevention Evaluation of Footwear Diabetes: Foot Exam Goal Achievement in Diabetes How Well Are We Doing? NHANES * Diabetes Management Is Changing New oral agents: DPP-4 inhibitors, SGLT-2 inhibitors, multiple combinations (metformin, SU, TZD) Additional injectable options: New insulins: basal, long-acting basal, ultra-rapid New GLP-1 RAs with longer half-life New insulin/glp-1 RA combinations Goals of today s discussion: Review the most current understanding of T2DM pathophysiology and its implication on treatment options Apply treatment strategies to patient scenarios *Data from separate studies. BP = blood pressure; LDL-C = low-density lipoprotein cholesterol; NHANES = National Health and Nutrition Examination Survey. Ali MK et al. N Engl J Med. 2013;368: Stark Casagrande S et al. Diabetes Care. 2013;36: Explore patient engagement techniques to help with medication and goal selection, and improve adherence The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance 1,2 Islet cell dysfunction Glucagon (α-cell) * Reduced effect of insulin indicating insulin resistance Current Understanding of the Pathophysiology of T2DM and the Targets of Available Anti-Hyperglycemic Agents Glucose output Liver Pancreas Insulin (β-cell) Hyperglycemia * Glucose uptake Muscle 1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36: Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

4 Insulin (mu/l) Insulin (mu/l) Effective and Timely Management of Patients with T2DM: A Case-based Approach Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes Glucose, mg % Meal Type 2 diabetes Normal patients Multiple Metabolic Abnormalities Contribute to Hyperglycemia in T2DM b-cell Impaired Insulin Secretion Increased Glucose Reabsorption Neurotransmitter Dysfunction Insulin, μ/ml a-cell Increased Glucagon Secretion Rapid Gastric Emptying Glucagon, 120 μμ/ml Increased HGP Decreased Glucose Uptake Increased Lipolysis Reduced Incretin Effect n=12 normal; n=12 type 2 diabetes (minutes) Insulin Resistance Adapted with permission in 2005 from Müller WA et al. N Engl J Med. 1970;283: Copyright 1970 Massachusetts Medical Society. All rights reserved. Adapted from DeFronzo RA. Diabetes. 2009;58: Incretins Role of Incretins in Glucose Homeostasis Gut-derived hormones, secreted in response to nutrients, that potentiate insulin secretion and suppress glucagon secretion in a glucose-dependent fashion Many other tissue effects Two predominant incretins Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) Rapidly inactivated by dipeptidyl peptidase-4 Incretin effect is impaired in type 2 diabetes 1. Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s Meier JJ et al. Diabetes Metab Res Rev. 2005;21: GI tract Ingestion of food Release of gut hormones Incretins 1,2 Active GLP-1 & GIP Inactive GLP-1 DPP-4 enzyme Inactive GIP Pancreas 2,3 Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose dependent Glucagon from alpha cells (GLP-1) DPP-4 = dipeptidyl-peptidase 4 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20: Ahrén B. Curr DiabRep. 2003;2: Drucker DJ. Diabetes Care. 2003;26: Holst JJ. Diabetes Metab Res Rev. 2002;18: Glucose uptake by muscles 2,4 Glucose production by liver Blood glucose Reduced Incretin Effect in Type 2 Diabetes Patients Incretin Therapies to Treat T2DM 80 Control Subjects Intravenous Glucose Oral Glucose 80 Type 2 Diabetes Patients Incretin effect is impaired in T2DM Natural GLP-1 has extremely short half-life * * * * * * * Time (min) Reprinted with permission from Nauck M et al. Diabetologia. 1996;29: * * * Time (min) Add GLP-1 analogues with longer half-life: Injectables Liraglutide Lixisenatide Albiglutide Dulaglutide Exenatide Exenatide QW Drucker. Curr Pharm Des. 2001;7: Drucker. Mol Endocrinol. 2003;17: Block DPP-4, the enzyme that degrades GLP-1: Oral agents Sitagliptin Saxagliptin Linagliptin Alogliptin 4

5 DPP-4 Inhibitors and GLP-1 RAs: Summary of Efficacy and Other Considerations Glucose Control by the Kidney GLP-1 RAs Mode of administration Injectable Oral Efficacy: HbA1C reduction DPP-4 Inhibitors 0.5%-2.0% ~0.5%-0.9% Effect on weight Potential for loss Neutral Hypoglycemia risk None, unless used with secretagogue or insulin None, unless used with sulfonylurea Renal considerations None None for linagliptin Other considerations CV -, C-cell hyperplasia and CV?, rare instance of medullary cancer in Stevens-Johnson, no rodents, pancreatitis risk not proven pancreatitis risk seen in large databases Gluconeogenesis Proximal tubule Renal contribution more substantial than previously believed 20% of post-absorptive total-body glucose release 40% of gluconeogenesis Reabsorption of filtered glucose >99% of glucose in glomerular filtrate is reabsorbed in the proximal renal tubule Sodium-coupled glucose co-transporters (SGLTs) transport glucose against gradient from lumen into epithelial cells Facilitated glucose transporters (GLUTs) transport glucose down gradient to plasma Marsenic O. Am J Kidney Dis. 2009;53: Bakris GL et al. Kidney Int. 2009;75: SGLT-2 Inhibitors: FDA Approved or in Clinical Development SGLT-2 Inhibitors for Treatment of Type 2 Diabetes Compounds in development Development status Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin LX4211 FDA APPROVED FDA APPROVED FDA APPROVED US Phase III clinical trials Approved for use in Japan Phase II clinical trials SGLT-2 inhibitors block reabsorption of filtered glucose in kidneys leads to glycosuria, improved glycemic control Benefits Insulin-independent action Calorie loss possible weight loss Low hypoglycemia Complement action of other anti-diabetic agents Can be used regardless of diabetes duration Side effects Recurrent UTI Genital fungal infection Decreased blood pressure Worsening of renal function # Increased hematocrit* Increased LDL-C* # Specific considerations for individuals with existing renal insufficiency, the elderly, and those receiving loop diuretics * Significance on patient outcomes is unclear at this time Kim Y et al. Diabetes Metab Syndr Obes. 2012;5: Pathophysiology and Pharmacologic Targets: Summary Several new agents have hit the market in recent years, providing increased ability to tailor treatments based on patient profiles Expanded treatment armamentarium allows for more personalized shared decision-making between PCP and patient Cases in Type 2 Diabetes Management 5

6 Case 1: Sophie Case 1: Reducing Hypoglycemic Risk Sophie is 87 years old and has had T2DM for 15 years Managed with glyburide 10mg BID since then with fairly good HbA1C levels Current concerns Recent episodes of confusion/dizziness Occasionally forgets medication and meals Home glucose monitoring shows multiple hypoglycemic episodes throughout day;? wrong dose of medication,? missing meals Case 1: Sophie cont d ADA/EASD Position Statement Physical examination Frail appearance (BMI: 19.0 kg/m 2 ) Rales at both lung bases posteriorly Bilateral 1+ pitting pedal edema Laboratory evaluation Random glucose: 68 mg/dl; HgbA1C: 6.1% SCr 1.7; egfr: 28 ml/min/1.73 m 2 Inzucchi SE et al. Diabetes Care. 2015;38: Used for Educational Purposes Only. *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22: Expected HbA1C Reduction of Antihyperglycemic Agents Drug Class Expected HbA1C Reduction Biguanide 1%-2% SU (2 nd Generation) 1%-2% TZD 1%-1.5% GLP-1 RA 0.5%-1.5% DPP-4 inhibitor 0.5%-1% SGLT-2 inhibitor 0.5%-1% Case 1: Sophie What Should You Consider? Her hypoglycemia risk Risk factors? Drug classes to avoid? Her renal insufficiency Drug classes to avoid? Required dose adjustments? Her preferences regarding route of administration Mayo Foundation for Medical Education and Research. Diabetes medication choice, Available at: Allen J, Freitas S. Comparison chart of glucose-lowering agents for management of type 2 diabetes mellitus. October

7 Cumulative 3-Year Incidence (%) Effective and Timely Management of Patients with T2DM: A Case-based Approach Hypoglycemia Risk Factors in Elderly Patients with T2DM The Association Between Medication-related Hypoglycemia and Vascular Risk Advanced age Polypharmacy Sulfonylurea or insulin use Poor nutrition or fasting Intercurrent illness Chronic renal disease Chronic liver disease Prolonged physical exercise Alcohol ingestion Endocrine deficiencies (thyroid, adrenal, pituitary) Loss of normal counter-regulation Hypoglycemic unawareness 40% 35% 30% 25% 20% 15% 10% 5% Hypoglycemia group P < P < % 30.65% 22.03% 17.48% 0% n=761 CVD Microvascular complications Mathieu C et al. Int J Clin Pract. 2007;61(suppl 154): Zhao Y et al. Diabetes Care. 2012;35: Sulfonylureas in Patients with Renal Impairment SUs are a leading cause of ER evaluations for adverse drug reactions Some SUs have prolonged half-life (glyburide, glimepiride) Some SUs have active metabolites that are renally excreted (glyburide) Safest may be glipizide (shortest acting and inactive metabolites) Consider glinides (eg, repaglinide, nateglinide) rapid-acting secretagogues Dose any secretagogue cautiously in CKD due to the fact that insulin itself is renally cleared Physicians' Desk Reference. 66th ed. Montvale, NJ: PDR Network; What about Metformin? FDA Changes Labeling for Metformin Use in T2DM Patients with Impaired Renal Function In T2DM patients with impaired renal function, use of metformin previously contraindicated systematic review assessing metformin-associated lactic acidosis risk in T2DM with impaired renal function: no increased rate of lactic acidosis, along with macrovascular outcome benefit 1 FDA: can use metformin safely in patients with mild renal impairment and in some with moderate renal impairment 2 FDA new labeling changes 2 Obtain egfr before starting metformin, then annually; assess more frequently if risk for renal impairment (eg, elderly) 2 Starting metformin in patients with egfr of 30 ml/min/1.73 m 2 not recommended Contraindicated in patients with egfr of <30 ml/min/1.73 m 2 Assess benefit and risk if egfr decreases to <45 ml/min/1.73 m 2 ; discontinue if egfr decreases to <30 ml/min/1.73 m 2 1. Inzucchi SE et al. JAMA. 2014;312: FDA Drug Safety Communication, ; Diabetes and Renal Impairment Profiles of Antidiabetic Medications Metformin: contraindicated when egfr <30, do not start if SU: dose reduction or replacement for renal insufficiency; do not use glyburide Insulin: dose reduction for renal insufficiency GLP-1 receptor agonists Exenatide: do not use if egfr <30 Others: use with caution DPP-4 inhibitors Sitagliptin, saxagliptin, alogliptin require dose adjustment Linagliptin: no dose adjustment SGLT-2 inhibitors Canagliflozin: lower dose for egfr 45-60; discontinue/do not initiate if egfr <45; contraindicated <30 Dapagliflozin do not initiate if egfr <60; discontinue if persistently <60; contraindicated in severe renal impairment, ESRD, dialysis Empagliflozin: do not initiate if egfr <45; discontinue if persistently <45; contraindicated in severe renal impairment, ESRD, dialysis Physicians' Desk Reference. Montvale, NJ: PDR Network; 2014; FDA FDA Drug Safety Communication, ; Of the recommended options for this patient, the DPP-4i class is associated with the fewest cautions. 7

8 Sitagliptin vs Glipizide Added on to Metformin Comparison of DPP-4 Inhibitors Glipizide 10mg twice daily (n=584) Sitagliptin 100mg once daily (n=588) Baseline + sd *P<0.001 between treatment Week 52 + sd Change in A1C from Baseline Hypoglycemia Weight % 32% (657 events) +1.1 kg* ) -0.67% 5% (50 events)* -1.5 kg Sitagliptin Saxagliptin Linagliptin Alogliptin 25, 50, 100 mg 2.5, 5.0 mg Dosage 5 mg once daily 25 mg once daily once daily once daily Half-life (t 1/2) 12.4 h 2.2 to 3.8 h >113 h 21 h 24-h DPP-4 80% 5 mg: 55% >90% >80% inhibition Kidney Liver and kidney Elimination Liver, <5% renal Renal (mostly unchanged) active metabolite Dose adjustments for renal Yes Yes None Yes impairment Drug interaction potential Low Strong CYP3A4/5 inhibitors Strong CYP3A4/5 inhibitors Low Nauck MA, et al. Diabetes Obes Metab. 2007;9: Summary Factors to consider when selecting a therapy: Hypoglycemia Risk factors: older age, concurrent medications (SUs, insulin), comorbidities Drug classes to avoid: SUs, insulin Comorbidity: Renal Insufficiency Metformin contraindicated SGLT-2 inhibitors not effective DPP-4 inhibitors: acceptable, require dose adjustment (linagliptin exception) GLP-1-RAs use cautiously Route of administration: injectable vs oral Case 2: Reducing Cardiovascular Risk Case 2: Manuel 56-year-old man with newly diagnosed T2DM Physical examination Patient is overweight (BMI: 31 kg/m 2 ) Laboratory evaluation Blood pressure: 153/87 mm Hg 10-year history of uncontrolled hypertension; patient is not compliant with prescribed antihypertensive medication FPG: 145 mg/dl HbA1C: 8.9% egfr: 60 ADA/EASD Position Statement Inzucchi SE et al. Diabetes Care. 2015;38: Used for Educational Purposes Only. *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22:

9 Case 2: Manuel Treatment Case 2: Manuel cont d Patient is placed on metformin (500 mg BID) and a TZD Patient experiences an MI Laboratory evaluation immediately following MI: Blood pressure: 155/85 mm Hg Total cholesterol: 246 mg/dl HbA1C: 8.5% Decline in renal function to 52 Also showing signs of CHF: chest pain, dyspnea, fatigue, persistent cough with phlegm production, ankle edema What is the next step regarding treatment for T2DM based on CV event? Would you stop the metformin and/or the TZD? T2DM Agents: CV Advantages and Disadvantages Large CV Outcomes Trials in Diabetes Class CV Advantages CV Disadvantages Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP-4- saxagliptin alogliptin sitagliptin linagliptin linagliptin inhibitors SUs? CVD events ischemic preconditioning Comparator placebo placebo placebo sulfonylurea placebo n 16,500 5,400 14,000 6,000 8,300 Results Biguanides LDL, CRP, insulin Study EMPA-REG CANVAS DECLARE VERTIS CV Study SGLT-2 empagliflozin canagliflozin dapagliflozin ertugliflozin TZDs HDL; TG, insulin, CRP, CVD events (pio) HF, LDL,?CVD events (rosi) inhibitors Comparator placebo placebo placebo placebo n ,300 22,200 8,000 GLP-1 RAs weight, BP, TG, CRP,? direct cardiac effect HR Results Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND GLP-1 RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide DPP-4 inhibitors? direct cardiac effect (via GLP-1)? HF Comparator placebo placebo placebo placebo placebo n 16,500 14,000 6,000 5,400 8,300 Courtesy, S. Inzucchi, Yale University Results EMPA-REG Study 7,034 T2DM patients at high CVD risk randomized to empagliflozin or placebo 1 Empagliflozin reduced primary major adverse cardiac event endpoint (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14% 1 38% reduction in CV mortality 35% reduction in hospitalization for heart failure Multiple metabolic benefits: decreases in HbA1C, weight, and BP; increase in HDL 1 Also associated with slower progression of renal disease 2 1. Abdul-Ghani M. Diabetes Care. 2016;39: ; 2. Wanner C et al. N Engl J Med. 2016;Jun 14. [Epub ahead of print]. Genital infections Other Considerations with SGLT-2 Inhibitors Patients treated with antifungal or antibiotic agents Fracture Use of dapagliflozin in moderate renal impairment leads to increased fractures Bladder cancer? Only seen in dapagliflozin study; groups had higher than expected risk of bladder cancer; possibly b/c GU SE led to increased cancer detection Serious urinary tract infections FDA warning due to reported cases of urosepsis Ketoacidosis Insulin-deficient patients at higher risk 12/2015: FDA recommends stopping the drug and immediately seeking treatment for symptoms of ketoacidosis Acute kidney injury Recent label change; 101 cases reported Leg/foot amputations FDA warning: canagliflozin associated with increased leg/foot amputations 9

10 Liraglutide Decreases CVD in High-risk Patients with T2DM in the LEADER Trial 9,340 adults with T2DM at high risk of major CVD randomized to liraglutide or placebo Results: liraglutide reduced primary endpoint by 13% (composite outcome of first occurrence of CV death, non-fatal MI, or non-fatal stroke) 15% reduction in all-cause death 22% reduction in CV death 14% relative risk reduction in MI 14% relative risk reduction in stroke 22% reduction in renal events Metabolic benefits: decreases in HbA1C, weight, BP Short-, Long-, and Very Long-acting GLP-1 RAs Parameters Short-acting Long-acting Very Long-acting Compounds Exenatide Liraglutide, Lixisenatide FBG = fasting blood glucose; PP = postprandial; QW = once weekly Albiglutide, Dulaglutide, Exenatide QW Half-life 2-5 hours hours >1 week Frequency of administration Twice daily Once daily Once weekly HbA1C reduction 0.7% 1.7% 0.8% 1.8% 0.8%-0.9% albiglutide 0.7% 1.6% dulaglutide 1.3%-1.9% exenatide QW FBG levels reduction Modest Strong Strong PP hyperglycemia Strong Modest Modest Glucagon secretion Reduction Reduction Reduction Gastric emptying rate Deceleration Some deceleration Some deceleration Blood pressure Reduction Reduction Reduction Body weight reduction 1-5 kg 2-4 kg kg Marso SP et al. N Engl J Med. 2016;Jun 13. [Epub ahead of print]. Presentation at ADA Scientific Sessions, June 13, 2016, session 3-CT-SY24. Meier JJ. Nat Rev Endocrinol.2012;8: Physician s Desk Reference. Montvale, NJ. Thomson PDR; Other Considerations with Incretin Agents No added hypoglycemia unless used with secretagogue or insulin Pancreatitis: FDA: available data do not confirm causal relationship between GLP-1 therapies and increased risk for pancreatic side effects Conclusion of meta-analysis of case-controlled and retrospective cohort studies (1,324,515 patients): no suggestion that acute pancreatitis is associated C-cell hyperplasia and medullary cancer in rodents Side effect with GLP-1 RA: nausea/vomiting Is insulin the best choice for this overweight patient, with CV history and increased hypoglycemia risk? FDA. FDA Drug Safety Communication Available at: Brooks M. FDA sides with EMA on incretin diabetes drugs Available at: Wang T et al. Diabetes Obes Metab. 2015;17: Chang CH et al. Medicine (Baltimore). 2016;95:e2603. Deciding about First Injectable Drug for Patients Not Controlled by Oral Agents DURATION-3 trial of once-weekly exenatide vs insulin glargine as first injectable therapy NR = not reported. 3-year endpoint Diamant M et al. Lancet. 2014:2: Exenatide (n=233) Insulin glargine (n=223) P Value Change in A1C -1.01% -0.81% 0.03 Change in body weight Hypoglycemia (exposureadjusted events) -5.5 lbs +4.4 lbs < events per patient-year 0.9 events per patient-year NR A1C: Effects of Adding GLP-1 RAs vs Basal Insulin to Multiple Oral Agents GLAR EXN BID LIRA P< vs insulin P<0.05 vs insulin P= vs insulin P=NS vs insulin -1.5 Noninferior vs insulin Heine R et al. Ann Intern Med. 2005;143: Davies M et al. Diabetes Obes Metab. 2009;11: Russell-Jones D et al. Diabetologia. 2009;52: Diamant M et al. Lancet. 2010;375: Davies M et al. Diabetes Care. 2013;36: EXN QW A1C (%) IDET MET ± SU* (n=216) MET ± SU (n=456) MET + GLIM (n=576) 2-3 OADs (n=235) MET + SU (N=535) * 70% on MET + SU background 70% on MET monotherapy background 10

11 Case 2: Manuel cont d Dose of metformin increased to 1000 BID Patient placed on liraglutide 0.6 mg per day for first 2 weeks, then increased to 1.2 mg Patient started on new antihypertensive medication and agent for dyslipidemia by cardiologist Laboratory values at 3 months: Blood pressure: 135/79 mm Hg Total cholesterol: 210 mg/dl HbA1C: 7.9% Weight loss: 18 lb What does the endocrinologist expect of the PCP regarding the ongoing management of this patient? Summary Antihyperglycemic agents have variable effects on CV outcomes in T2DM SGLT-2 inhibitors Associated with weight loss, BP reduction Empaglifozin: favorable CV outcomes DPP-4 inhibitors Neutral CV effects GLP-1 RAs Effective lowering of A1C (except albiglutide) Weight loss, BP reductions, small improvements in lipids Liraglutide demonstrated CV risk reduction Case 3: Barbara Case 3: Initiation and Intensification of Insulin 52-year-old woman with 6-year history of T2DM Also has hypertension and dyslipidemia, both controlled on medications; no history of CVD Takes metformin 1,500 mg QD and glimepiride 8 mg QD A1C was 8.2%, but has increased to 9.1%; patient reports compliance with antihyperglycemic medications, but has experienced several episodes of dizziness and fatigue over past month Weight = 186 lb, height = 5 7 (BMI = 29.1 kg/m 2 ) ADA/EASD Position Statement When to Consider Insulin in a Person with Type 2 Diabetes Consider as initial therapy in T2DM if A1C >9% or symptomatic When a combination of non-insulin antihyperglycemic medications are unable to achieve A1C target Unacceptable side effects and/or contraindications to non-insulin medications Advanced hepatic or renal disease or other comorbidities precluding use of other agents Special considerations (steroids, infection, pregnancy) Hyperglycemia in a hospitalized patient Severely uncontrolled diabetes* * Random Glucose >300 mg/dl, A1C >10%, Ketonuria, Symptomatic polyuria/polydipsia, weight loss Inzucchi SE et al. Diabetes Care. 2015;38: Used for Educational Purposes Only. *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22: Nathan DM et al. Diabetes Care. 2009;32: Inzucchi SE et al. Diabetes Care. 2012;35: ADA. Diabetes Care. 2014:37(Suppl 1):S14-S80. 11

12 Plasma insulin levels Effective and Timely Management of Patients with T2DM: A Case-based Approach ADA/EASD Position Statement Initiation and Adjustment of Insulin Regimens: Basal Insulin (Analog or NPH) Basal Insulin (usually with metformin +/- other noninsulin agent) Start: 10 U/day or U/kg/day Adjust: 10%-15% or 2-4 U once-twice weekly to reach FBG target For hypo: Determine and address cause; dose by 4 U 10%-20% Insulin Preparations: Onset and Duration of Action Insulin preparation Onset of action Peak Duration of action Glargine (U-100) 45 min 4 hr Minimal depends on dose Up to 22 hr Glargine (U-300) ~6 hr Minimal depends on dose >24 hr Detemir 45 min 4 hr Minimal depends on dose Up to 22 hr Degludec (U-100/U-200) 1 hr Minimal depends on dose >42 hr Degludec/aspart 70/30 Rapid after injection Minimal depends on dose >24 hr Add 1 rapid insulin injection before largest meal If not controlled after FBG target is reached (or if dose >0.5 U/kg/day), treat PPG excursions with mealtime insulin, (consider initial GLP-1 RA Trial) Change to premixed insulin twice daily Analogue Biphasic / Premixed Insulin Insulin preparation Onset of action Prandial Peak Duration of action 75% NPL / 25% Lispro ~15 min 1-2 hr % NPL / 50% Lispro ~15 min 1-2 hr % Aspart protamine / ~15min 4-10 hr % Aspart Inzucchi SE et al. Diabetes Care. 2015;38: *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22: Time-Action Profiles of Human Insulins and Insulin Analogs Long-acting Insulins Inhaled insulin Aspart, Glulisine, Lispro Regular Insulin NPH Detemir (basal) Glargine (basal) Intermediate-acting insulin: NPH Long-acting insulin: Detemir, Glargine Glargine U-300 Degludec U-100 or U Time Course of Action (Hour) Time after SC injection (hours) Rosenstock J et al. eds. Textbook of Type 2 Diabetes. 2003: Plank J et al. Diabetes Care. 2005;28: Rave K et al. Diabetes Care. 2005;28: ; Afrezza (insulin human). Prescribing information. Available at: Adapted from Hirsch I. N Engl J Med. 2005;352: Insulin Glargine U-300 Once-daily long-acting basal insulin FDA approved 02/25/2015 Trials comparing glargine U-300 with glargine U-100 Similar rates of glucose control and HbA1C reduction Lower rates of nocturnal and severe hypoglycemia with U-300 U-300 has longer duration of action compared with U-100 U-300 has flatter pharmacokinetic profile compared with U-100 Riddle MC et al. Diabetes Care. 2014;37: ; Yki-Järvinen H et al. Diabetes Care. 2014;7: ; Bolli GB et al. Diabetes Obes Metab. 2015;17: Insulin Degludec New-generation ultra-long-acting basal insulin analog FDA approved 09/25/2015 Meta-analysis of treat-to-target trials (2,899 people randomized to insulin degludec and 1,431 randomized to insulin glargine) Lower hypoglycemia* in T2DM RR = 0.83 [95% CI: 0.74; 0.94] 86% reduction in insulin-naive patients Lower nocturnal hypoglycemia** in T2DM RR: 0.68 [95% CI: 0.57; 0.82] Lower hypoglycemia rate in elderly Improved treatment satisfaction and quality of life FLEX Study: time of daily dosing can be varied without compromising glycemic control with A1C reduction comparable to fixed time glargine * Plasma glucose <3.1 mmol/l, irrespective of symptoms, or if the hypoglycemia was severe requiring assistance from a third party); ** Nocturnal hypoglycemia was defined as occurring between 00:00 and 05:59. Evans M, McEwan P. J Comp Eff Res. 2015:1-8. [Epub ahead of print]. Ratner R et al. Diabetes Obes Metab. 2013;15: Meneghini L et al. Diabetes Care.2013;36:

13 Ultra-long Basal Insulins: Place in Therapy Patients needing less fluctuation of insulin levels Includes those with: Nocturnal hypoglycemia Renal impairment, elderly Variable schedules/lifestyle: shift workers, college students Complaints of variability of fasting glucose levels Adherence issues: can dose within 8 hours if dose was missed Insulin Glargine Follow-on (Biosimilar) Agent FDA approved first follow-on insulin glargine agent in December 2015 Also referred to as biosimilar Long-acting alternative form of currently available insulin glargine with the same protein sequence and similar glucose-lowering Injected once daily, subcutaneously using a prefilled pen formulation May be priced competitively Availability for use in US: late 2016 FDA news release, Case 3: Barbara cont d She has not met her A1C goal of <7% despite 56 units of glargine daily and metformin 1000 BID She has had several episodes of nocturnal hypoglycemia in the last month, so she started to reduce her glargine dose on her own What are some reasons she hasn t gotten to goal? ADA/EASD Position Statement Options when Basal Insulin +/- OADs Don t Achieve Target Glycemia 2 3+ Add 1 rapid insulin* injection before largest meal Start: 4U, 0.1 U/kg, or 10% basal dose If A1C <8%, consider basal by same amount Adjust: dose by 1-2 U or 10%-15% oncetwice weekly until SMBG target reached For hypo: Determine and address cause; corresponding dose by 2-4 U 10%-20% more flexible If not controlled, consider basalbolus Inzucchi SE et al. Diabetes Care. 2015;38: *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22: If not controlled after FBG target is reached (or if dose >0.5 U/kg/day), treat PPG excursions with mealtime insulin, (consider initial GLP-1 RA trial) Add 2 rapid insulin* injection before largest meal ( basal-bolus ) Start: 4 U, 0.1 U/kg, or 10% basal dose/meal If HbA1C <8%, consider basal by same amount Adjust: dose by 1-2 U or 10%-15% once-twice weekly until SMBG target reached For hypo: Determine and address cause; corresponding dose by 2-4 U 10%-20% Change to premixed insulin* twice daily Start: Divide current basal dose into 2/3 AM, 1/3 PM or ½ AM, ½ PM Adjust: dose by 1-2 U or 10%-15% once-twice weekly until SMBG target reached. For hypo: Determine and address cause; corresponding dose by 2-4 U 10%-20% If not controlled, consider basalbolus less flexible mod. high Addition of GLP-1 RAs vs Prandial Insulin to Basal Insulin Outcome LIRA QD vs ASP EXN BID vs LIS TDS 2 ALBI QW vs LIS QD 1 TID 3 Δ A1C (%) 0.7 1,a 0.4 1,a 1.1 2,b 1.1 2,b 0.8 3,c 0.7 3,c Δ Weight (kg) 2.8 d d 0.7 d 0.8 Hypo (EPY) e 1.0 d,f f Nausea (%) LIRA > ASP (first 2 wk) DULA is approved only with prandial insulin; EXN QW is not approved with any insulin 4,5 a Added to DEG (26 wk; n = 177); DEG is not approved by the US FDA 1. Mathieu et al. Diabetes Obes Metab. 2014;16: b Added to GLAR (30 wk; n = 637) 2. Diamant et al. Diabetes Care. 2014;37: c Added to GLAR (26 wk; n = 566) 3. Rosenstock et al. Diabetes Care. 2014;37: d P <0.05 between groups 4. Eli Lilly and Co. Trulicity (dulaglutide) prescribing information. e Rates of severe hypoglycemia were low across groups f Lower levels of nocturnal hypoglycemia 5. US FDA. Drugs@FDA. GLP-1 RA Fixed-Ratio Co-formulations: Emerging Basal Insulin a Not US FDA approved b 26-week open-label, treat-to-target RCT; n = 1663 (insulin naïve) c 24-week open-label, treat-to-target RCT; n = 323 (insulin naïve) d P<0.001 vs ideglira e P<0.001 vs iglarlixi Outcome Δ A1C (%) Δ Weight (kg) IDegLira 1,a,b 1.9* 0.5* DEG 1,a,b 1.4* 1.6*,d LIRA 1,b 1.3* 3.0*,d iglarlixi 2,a,c GLAR 2,c ,e *Non-inferior to DEG, superior to LIRA Superior to GLAR 3 severe hypoglycemic episodes per group Lower rate of hypoglycemia (overall and nocturnal) for LIRA vs DEG or IDegLira 1 Lower rate of hypoglycemia (overall) for iglarlixi than for GLAR 2,e Current GLP-1 RAs should not be mixed with or injected adjacent to insulin 3 1. Gough SC et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J et al. Diabetologia. 2014;57(suppl 1) [abstract 241]. 3. US FDA. Drugs@FDA. 13

14 GLP-1 RA + Prandial Insulin vs Basal Insulin + Prandial Insulin a P <0.05 for both -1.2 DULA groups vs GLAR Δ A1C (%) With GLP-RA vs basal insulin: Lower rates of nocturnal hypoglycemia b (and total hypoglycemia b with DULA 1.5 mg vs basal insulin) Less weight gain DULA QW (0.75 mg) DULA QW (1.5 mg) GLAR QD Higher rates of GI adverse effects (nausea, vomiting, dyspepsia, diarrhea) Concentrated Insulins: Guidance on How to Change to and from Formulations Dose differences in general: U-300 glargine > U-100 glargine > U-100/U-200 degludec Current Insulin U-100 Glargine Change to U100/U-200 Degludec Consider decreasing dose by 10% Change to U-300 Glargine No dose change at initial change; will probably need to up-titrate Change to U-100 Glargine U-300 Glargine Decrease dose by 20% Decrease dose by 20% U100/U-200 Degludec Current Insulin Change to U100/U-200 Degludec No dose change at initial change; will probably need to up-titrate Change to U-300 Glargine No dose change at initial change; will probably need to up-titrate Change to U-100 Glargine a BL A1C, 8.4%-8.53%; used with LIS TID (52 weeks; n=884); b BG 70 mg/dl and/or symptoms Blonde L et al. Lancet. 2015;385: Case 3: Barbara cont d Her glargine was changed to degludec at 50 units. She continued her metformin at 500 BID and was started on 0.75 mg dulaglutide weekly Diet and exercise options were again reviewed with the patient. She promised to walk several times a week with a friend Follow-up 3 months later: she did not report any hypoglycemic episodes. Patient had lost 14 lb. Her A1C was 7.4%; her dulaglutide dose was increased to 1.5 mg/weekly What does the endocrinologist expect of the PCP regarding the ongoing management this patient? Summary of Intensification of Treatments Hypoglycemia often limits intensification of insulin regimen Consider metformin, TZDs, ultra-long acting insulins, SGLT-2 inhibitors, and incretin agents Per ADA guidelines, if basal insulin dose becomes excessive, consideration should be given to use GLP-1 RA or bolus insulin with 1-3 meals daily What Is Clinical Inertia? A wait until next visit approach: Practitioners recognize poor control... Patient Engagement to Overcome Barriers, Minimize Risk, and Improve Adherence AND Agree medication should be intensified... YET TAKE NO ACTION CAUSES: Clinician overestimation of care provided Use of soft reasons to avoid intensification of therapy Lack of education, training, and practice organization Phillips LS et al. Ann Intern Med. 2001;135:

15 Reasons for Clinical Inertia Provider Time constraints Lack of knowledge Potential risks of hypoglycemia Variations in guideline recommendations Patient Nonadherence Concerns about hypoglycemia and weight gain Healthcare System Cost of newer medications Khunti K, et al. Br J Diabetes Vasc Dis. 2015;15: Cost of Clinical Inertia Retrospective cohort study using UK Clinical Practice Research Datalink 105,477 newly diagnosed T2DM patients from 1990; follow-up data until 2012 Mean A1C at diagnosis: 8.1% 11% history of CVD; 7.1% experienced 1 CV event during 5.3 years median follow-up One year delay in receiving intensified therapy (goal A1C <7.0%) associated with significantly increased MI by 67% Stroke by 51% HF by 64% Composite CVE by 62% Paul S et al. Cardiovasc Diabetol. 2015;14:100. Published online 2015 Aug 7. doi: /s x. Decisions Need To Be Shared Goal of shared decision-making (SDM): ensure that treatment decisions align with patient s preferences Often includes patient education and decision-support tools Becomes a partnership between clinician and patient Potential benefits of SDM in T2DM Patients have vested interest in their care Increased patient knowledge Less anxiety over the process of care Improved health outcomes Reductions in inappropriate costs Responding to Patient Fears and Misconceptions about Insulin/Injections 50% fear injection I don t like needles Start with 1 injection a day and have patient self-inject in office Prescribe pens Teach breathing or forceful exhalation during injection to reduce anxiety/pain perception <10% of insulin-naïve patients feel insulin is beneficial Explain that In past, insulin started too late, so complications already occurred Clinical trials show benefit of glucose control in decreasing microvascular complications Lee EO et al. N Engl J Med. 2013;368:6-8. VA. Shared Decision Making with the Patient with Diabetes Responding to Patient Fears and Misconceptions about Insulin/Injections (cont d) 50% see insulin/injections as punishment and self-blame Explain that decrease in insulin production is natural progression of diabetes Cost Use formulary, coupons, pharma assistance How will it affect job, lifestyle T2DM is common; work together to work around schedule and work issues Fear of weight gain Chance of weight gain will decrease with healthy eating and daily activity Responding to Patient Fears and Misconceptions about Insulin/Injections (cont d) Fear of hypoglycemia It doesn t take much to turn a patient off after an episode of hypoglycemia Patients often auto-correct too much to prevent this Creates spiral of inadequate control What we can do: Use newer insulins/agents with less hypoglycemia Loosen A1C target, encourage home glucose monitoring Teach how to adjust When writing for insulin, always write for glucose tabs 15

16 Rule of 15 for Treating Hypoglycemia Guide for Patients If BG is mg/dl take 15 grams of simple sugar, such as 4 oz of juice or 4 glucose tablets ALWAYS CARRY SOMETHING Then eat snack with 15 grams of carbohydrates and a protein Combine with protein Drink lots of water If less than 50 mg/dl take 30 grams of simple sugar, such as 8 oz of juice or 8 glucose tablets; then use the same instructions Check sugar frequently it will go up before they feel better! IMPORTANT: If they eat grams of carbohydrates, they need to take insulin to cover these carbs, or their glucose will go very high Medline Plus. Accessed: 12/5/2015. Compliance with T2DM Medications: Injection vs Oral Therapy % of Patients with <80% Compliance 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 2.3% Albiglutide HARMONY 3 Trial (Week 156) HARMONY 5 Trial (Week 156) HARMONY 8 Trial (Week 52) 20% 20% 18.2% 18% 18% 1.0% Placebo (injection) 7.5% 7.6% Glimepiride Sitagliptin 9.2% Placebo (oral) Leiter LA et al. ADA 2014 Annual Meeting. Abstract 994-P. 16% 14% 12% 10% 8% 6% 4% 2% 0% 2.2% 0.8% 14.9% 16% 14% 12% 10% 8% 6% 4% 2% 0% 1.6% 1.6% 11.4% 14.8% Facilitating Behavior Change Beyond the Doctor Create a Team Approach Enhancing Patient Engagement in Diabetes Care PATIENT-CENTERED COMMUNICATION Focus on the person, not the disease Explore feelings, identify barriers Guilt, anger, depression, helplessness, costs, pill burden, lack of insight Adapted from Funnell MM. Fam Pract. 2010;27: i17 i22. GOAL-SETTING MODEL Explore the problem Develop a plan together Commit to action Experiment with, re-evaluate the plan COMMUNICATION MODEL Ask-Listen-Empathize-Encourage Use plain language Ask open-ended questions Reflect on areas of concern Identify actions to address the problem or issue (e.g. cost get pharma help, coupons) Involve the patient in all aspects of care Help overcome social, cultural, linguistic barriers Maximize involvement of other team members Community Health Workers Case Managers Adapted from Baig AA et al. Med Care Res Rev. 2010;67(5 Suppl):163S-197S. Clinician + Patient Pharmacistled Medication Management Medical (or Medication) Assistance Programs Summary We know from DCCT and UKPDS that sustained intensification of therapy is difficult Embrace ADA recommendations to reduce complications Don t be afraid to consider new combinations and treatment options Engage your patient in treatment decisions We hold the key to our patient s success! Thank you! 16