Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME

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1 Developed Through a Strategic Partnership Between AACE and Medscape Education Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME Supported by independent educational grants from Merck & Co., Inc.; Novo Nordisk Pg.1

2 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME This article is a CME certified activity. To earn credit for this activity visit: CME Released: 5/1/2017; Valid for credit through 5/1/2018 Target Audience This activity is intended for diabetologists and endocrinologists, primary care physicians, and cardiologists who treat patients with type 2 diabetes (T2D). Goal The goal of this activity is to increase awareness of the updated 2017 American Association of Clinical Endocrinologists/American College of Endocrinology consensus statement on the comprehensive treatment of T2D and use it to develop individualized patient care plans. Learning Objectives Upon completion of this activity, participants will: Have increased knowledge regarding the: Updated guideline recommendations for T2D treatment Have greater competence related to: Individualize treatment strategies for complex patients with T2D Credits Available ACCME - maximum of 1.0 AMA PRA Category 1 Credit(s) Accreditation Statements For Physicians Provided by the American Association of Clinical Endocrinologists The American Association of Clinical Endocrinologists is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The American Association of Clinical Endocrinologists (AACE) designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. For questions regarding this CME activity, please contact: AACE CME Department Phone: (904) cme@aace.com For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact CME@medscape.net Pg.2

3 Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information about your eligibility to claim credit, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent participating in the activity. To successfully earn credit, participants must complete the activity online during the credit eligibility period that is noted on the title page. Follow these steps to claim a credit certificate for completing this activity: 1. Read the information provided on the title page regarding the target audience, learning objectives, and author disclosures, read and study the activity content and then complete the post-test questions. If you earn a passing score on the post-test and we have determined based on your registration profile that you may be eligible to claim CPD credit for completing this activity, we will issue you a CPD credit certificate. 2. Once your CPD credit certificate has been issued, you may view and print the certificate from your CME/CE Tracker. CPD credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing Edit Your Profile at the top of the Medscape Education homepage. We encourage you to complete an Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing Edit Your Profile at the top of your Medscape homepage. The credit that you receive is based on your user profile. Pg.3

4 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME Faculty Information and Disclosure Statements Learner Bill of Rights The American Association of Clinical Endocrinologists (AACE) recognizes that you are a life-long learner who has chosen to engage in continuing medical education to identify or fill a gap in knowledge, skill, or performance. As part of AACE s duty to you as a learner, you have the right to expect that your continuing medical education experience with AACE includes: CONTENT that: Promotes improvements or quality in healthcare; Is valid, reliable, and accurate; Offers balanced presentations that are free of commercial bias for or against a product/service; Is vetted through a process that resolves any conflicts of interests of planners, teachers, or authors; Is driven and based on learning needs, not commercial interests; Addresses the stated objectives or purpose; and Is evaluated for its effectiveness in meeting the identified educational need. A LEARNING ENVIRONMENT that: Supports learners ability to meet their individual needs; Respects and attends to any special needs of the learners; Respects the diversity of groups of learners; and Is free of promotional, commercial, and/or sales activities. DISCLOSURE of: Relevant financial relationships planners, teachers, and authors have with commercial interests related to the content of the activity; and Commercial support (funding or in-kind resources) of the activity. DISCLAIMER FDA DISCLOSURE The contents of some CME/CE activities may contain discussions of non-approved or off-label uses of some agents mentioned. Please consult the prescribing information for full disclosure of approved uses. Declaration of Disclosure and Conflicts of Interest It is the policy of AACE to ensure balance, independence, objectivity, and scientific rigor in all of its CME activities. Presentation content may include discussion of an unlabeled or an investigational use of a product. AACE requires that participating faculty disclose to the audience any product(s) and its use(s) discussed in the educational activity that are unapproved/unlabeled for the use by the FDA or still considered investigational in nature. Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships. Relevant financial relationships are financial relationships in any amount occurring within the past 12 months that create a conflict of interest. AACE requires speakers, faculty, CME Committee, and other individuals who are in a position to control the content of this educational activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by AACE for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations. The intent of this disclosure is not to prevent a speaker with commercial affiliations from presenting, but rather to provide learners with information from which they may make their own judgments. Informed learners are the final safeguards in assuring that a CME activity is independent from commercial influence. AACE has reviewed all disclosures and resolved or managed all identified conflicts of interest for this educational activity, as applicable. Pg.4

5 Faculty Janet McGill, MD, MA, FACE Associate Professor of Medicine, Division of Endocrinology, Metabolism, and Lipid Research. Washington University, St. Louis, Missouri Disclosure: Janet McGill, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Boehringer-Ingelheim Pharmaceuticals, Inc.; Dexcom, Inc.; Dynavax Technologies Corporation; Intarcia Therapeutics, Inc.; Merck & Co., Inc.; Novo Nordisk; Valeritas, Inc. Served as a speaker or a member of a speakers bureau for: Dexcom, Inc.; Janssen Pharmaceuticals, Inc. Received grants for clinical research from: AstraZeneca Pharmaceuticals LP/Bristol-Myers Squibb Company; Dexcom, Inc.; Lexicon Pharmaceuticals, Inc./Sanofi; Novartis Pharmaceuticals Corporation Dr McGill does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr McGill does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. SD/Editor/Writer Information and Disclosure Statements Anne G. Le, PharmD, RPh Senior Scientific Director, Medscape, LLC Disclosure: Anne G. Le, PharmD, RPh, has disclosed no relevant financial relationships. Additional Planners/Reviewers Information and Disclosure Statements Christine Welniak Freelance Medical Writer Disclosure: Christine Welniak has disclosed no relevant financial relationships. Pg.5

6 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME The following cases are modeled on the interactive grand rounds approach. The questions within the activity are designed to test your current knowledge. After each question, you will be able to see whether you answered correctly and read evidence-based information that supports the most appropriate answer choice. The questions are designed to challenge you; you will not be penalized for answering the questions incorrectly. At the end of the activity, there will be a short post-test assessment based on the material presented. CASE 1: PATIENT HISTORY Larry is a 73-year-old man who was diagnosed with type 2 diabetes (T2D) 12 years ago. He also has hypertension, chronic kidney disease stage III, New York Heart Association class II heart failure (HF), and atrial fibrillation. He has developed some gastrointestinal (GI) complaints (diarrhea and some abdominal discomfort). He admits to occasional chest pain and shortness of breath. His glycated hemoglobin (HbA 1c ) is 8.4%, with fasting blood glucose of 156 to 179 mg/dl, currently treated with metformin 1000 mg twice daily. Question 1. What is the best description of the appropriate treatment goals for Larry s type 2 diabetes (T2D)? x Lower glycated hemoglobin (HbA 1c ) to less than 6.5% and minimize adverse events Lower HbA 1c to less than 7.0% and address comorbidities (eg, hypertension) Lower HbA 1c to 7.0% to 8.0% and minimize hypoglycemic risk Lower HbA 1c to around 8.0% and address comorbidities (eg, heart failure [HF]) Answer Explanation: A glycated hemoglobin (HbA 1c ) goal of between 7.0% and 8.0% may be considered for certain patient populations (eg, elderly patients who might be at risk for hypoglycemic episodes in the pursuit of more stringent HbA 1c control). Minimizing hypoglycemic risk is a priority for all patients with type 2 diabetes (T2D). Treatment Goals for Elderly Patients with T2D and Comorbidities Controlling glucose levels and minimizing hypoglycemic risk are cornerstones of T2D management. The 2017 consensus statement from the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) endorse individualizing treatment goals and management plans based on a patient s history, status, comorbidities, and risks. Glycated hemoglobin targets should consider a patient s age, comorbidities, risk for hypoglycemia, and patient motivation and adherence, among other factors. The recommended target HbA 1c for older patients and patients with a history of hypoglycemia, severe renal dysfunction, or several comorbidities is 7.0% to 8.0%. [1] Minimizing the risk for hypoglycemia is also a priority, particularly for elderly patients. Of note, severe hypoglycemia is more likely to occur during the pursuit of low HbA 1c targets. [1] Pg.6

7 Table 1. Key Principles of the AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm [1] Lifestyle therapy, including medically supervised weight loss, is key to managing T2D. The HbA1c target must be individualized. The choice of therapies must be individualized on basis of patient characteristics, impact of net cost to patient, formulary restrictions, personal preferences, etc. Minimizing risk of hypoglycemia is a priority. Minimizing risk of weight gain is a priority. This algorithm stratifies choice of therapies based on initial HbA 1c. Combination therapy is usually required and should involve agents with complementary actions. Comprehensive management includes lipid and blood pressure therapies and related comorbidities. AACE = Association of Clinical Endocrinologists; ACE = American College of Endocrinology; HbA 1c = glycated hemoglobin; T2D = type 2 diabetes. In the ACCORD randomized controlled trial (RCT) which enrolled middle-aged and elderly patients with T2D, intensive therapy (ie, target HbA 1c < 6.0%) resulted in higher mortality (hazard ratio of 1.22, P =.04) than did therapy (ie, target HbA 1c = 7.0%-7.9%), leading to early termination of ACCORD. [2] The incidence of hypoglycemia requiring assistance was significantly more frequent in the intensive therapy arm (P <.001) than in standard therapy arm. Although no correlation between hypoglycemia and mortality was found in long-term follow-up of ACCORD, [3] a retrospective analysis found that patients in the intensive treatment group who experienced severe, symptomatic hypoglycemia that required assistance had a mortality rate of 2.8% compared with 1.2% for individuals with no hypoglycemia in the intensive treatment group. [4] The standard therapy group showed a similar pattern, with mortality rates of 3.7% and 1.0% for patients with hypoglycemia and no hypoglycemia, respectively. [4] ACCORD was not the only RCT evaluating T2D management that documented higher mortality for individuals with hypoglycemia. Based on data from several RCTs, it is estimated that hypoglycemia increases mortality by 2- to 4-fold, [4,5] although the mechanism remains unclear. [4] AACE/ACE guidelines indicate that avoidance of both severe and nonsevere hypoglycemia should be a priority. [1] Case 1: History, Physical Examination, and Lab Results Larry wants to attend his grandson s wedding in 7 months. His daughter convinced him that he needs to prepare for the wedding by increasing his activity, watching his diet, and going to his doctor to optimize his treatment and address his symptoms. Pg.7

8 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME Table 2. History and Physical Examination History Problem list Family Social Past and current medications Other Recent Lab Work Findings Hypertension, CKD stage III, proteinuria, NYHA Class II HF, AF, T2D: duration 12 years Parents deceased. Father: hypertension, hyperlipidemia. Father died after an MI. Mother had T2D and AF and died after a stroke Retired, lives with wife, good social support Lisinopril 40 mg, furosemide 20 mg, carvedilol 12.5 mg, warfarin 5 mg, metformin 1000 mg twice daily Recent symptoms (diarrhea, abdominal discomfort) and mild neuropathy Findings HbA 1c 8.4% Fasting blood glucose Serum creatinine 1.67 LDL-C 77 HDL-C 43 Triglycerides 131 egfr 41 BUN 24 SGOT SGPT Physical Examination Vital signs General impression 166 to 195 mg/dl Normal Normal Findings BMI 28.9 kg/m 2 Skin Chest and lungs Abdomen Lower extremities 135/78 mm Hg; heart rate = 77 bpm Older gentleman, overweight, ambulatory Clear, no rash Heart: irregularly irregular with controlled rate; lungs are clear; 1+ LE edema Soft, tender to palpation, no masses Bilateral mild sensory deficit AF = atrial fibrillation; BMI = body mass index; BUN = blood urea nitrogen; CKD = chronic kidney disease; egfr = estimated glomerular filtration rate; HbA 1c = glycated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HF = heart failure; LDL-C = low-density lipoprotein cholesterol; LE = lower extremity; MI = myocardial infarction; NYHA = New York Heart Association; SGOT = serum glutamic oxaloacetic transaminases; SGPT = serum glutamic pyruvic transaminases; T2D = type 2 diabetes. Question 2. What is the appropriate next step with regard to Larry s antihyperglycemic treatment? x Continue with metformin, but decrease the dose and add a dipeptidyl peptidase-4 (DPP-4) inhibitor Switch to a DPP-4 inhibitor Switch to a sodium-glucose cotransporter 2 (SGLT2) inhibitor Switch to basal insulin Answer Explanation: A dipeptidyl peptidase-4 (DPP-4) inhibitor is the most appropriate antihyperglycemic therapy in the context of Larry s age, comorbidities, treatment goals, and kidney function. Pg.8

9 TREATMENT CHOICES FOR ELDERLY PATIENTS WITH COMORBIDITIES The AACE/ACE guidelines emphasize that attaining the HbA 1c target requires a nuanced approach that balances [a patient s] age, comorbidities, and hypoglycemia risk. [1] Thus, although the AACE/ACE recommend starting a patient with an HbA 1c greater than 7.5% on dual or triple therapy, it may be more reasonable to manage an elderly patient with elevated HbA 1c on monotherapy. The case patient is exhibiting symptoms suggestive of metformin intolerance (GI complaints and mild neuropathy). Metformin dosing should be adjusted down for patients with an estimated glomerular filtration rate (egfr) of 30 ml/min/1.73 m 2 to 45 ml/ min/1.73 m 2. (Metformin should not be initiated for patients with egfr <45 ml/min/1.73 m 2 and should not be used at all when the egfr is <30 ml/min/1.73 m 2.) [1] Metformin should be lowered to 500 mg twice daily. A long-acting formulation might help reduce GI symptoms. With an HbA 1c of 8.4%, additional therapy will be needed to reach even modified targets. Dipeptidyl peptidase-4 (DPP-4) inhibitors are well tolerated by patients and can be used even in the setting of renal dysfunction. [5] DPP-4 inhibitors are weight-neutral and are associated with a low risk for hypoglycemia. [1] Based on clinical studies, adverse events (AEs) associated with DPP-4 inhibitors are mild and similar to AEs experienced by patients taking placebo or the comparator drug [6] ; however, DPP-4 inhibitors should not be prescribed to patients with a history of pancreatitis. [1] By degrading glucagon-like peptide-1 (GLP-1), DPP-4 inhibitors augment insulin secretion and suppress glucagon secretion in a glucose-dependent manner. [7] Similar to other antihyperglycemic therapies, DPP-4 inhibitors tend to have more pronounced HbA 1c reduction in the setting of higher baseline levels. [6] Most clinical trials have evaluated DPP-4 inhibitors as an add-on to metformin. Thus, there is not a wealth of scientific evidence on DPP-4 inhibitor efficacy as monotherapy. According to one meta-analysis, DPP-4 inhibitor monotherapy lowered HbA 1c by about 0.9%, on average, compared with a mean reduction of 1.2% for metformin. [8] DPP-4 inhibitors can be used in patients with T2D with moderate renal impairment although the HbA 1c reduction is likely to be more modest, at an average of about 0.5%. [9] A sodium-glucose cotransporter 2 (SGLT2) inhibitor is not an appropriate choice for Larry because efficacy is diminished when egfr is less than 45 ml/min/1.73 m 2. [1] Insulin monotherapy could introduce hypoglycemia risk. [1] Table 3. Renal Function and Oral Antihyperglycemic Therapy [1] Dose adjustment needed Do not use Metformin DPP-4 Inhibitors GLP-1 RAs SGLT2 Inhibitors Yes, egfr = 30 to 45 ml/ Yes, for moderate and min/1.73 m 2 severe renal dysfunction Do not initiate in patients with egfr <45 ml/min/1.73 m 2 No dose adjustment needed for linagliptin NA NA Yes, egfr = 45 to 60 ml/min/1.73 m 2, do not use dapagliflozin; use the lower dose of canagliflozin Exenatide is contraindicated for use when CrCl <30 ml/min egfr <45 ml/min/1.73 m 2 Discontinue use if egfr <30 ml/min/1.73 m 2 CrCl = creatinine clearance; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; egfr = estimated glomerular filtration rate; NA = not applicable; RA = receptor agonist; SGLT2 = sodium-glucose cotransporter 2. Pg.9

10 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME Question 3: How confident are you in initiating or intensifying antihyperglycemic therapy for your patients with T2D? (Select ranking from 1 [Not confident] to 5 [Very confident]) Answer choices: 1 - Not confident Very confident Question Introduction: Larry is a 73-year-old man who was diagnosed with T2D 12 years ago. He also has hypertension, New York Heart Association class III HF, and atrial fibrillation. He has developed some gastrointestinal complaints (diarrhea, some abdominal discomfort). He admits to occasional chest pain and shortness of breath. Larry was recently discharged to a long-term care facility after a hospitalization for HF. His HbA 1c is 8.4% with fasting blood glucose of 156 to 179 mg/dl. Based on Larry s treatment goal of an HbA 1c less than 7% and kidney function, a DPP-4 inhibitor is the most appropriate antihyperglycemic therapy for Larry at this time. Question 4. Which would be the optimal antihyperglycemic therapy to prescribe for Larry? Alogliptin or linagliptin Linagliptin or saxagliptin Saxagliptin or sitagliptin x Linagliptin or sitagliptin Answer Explanation: Linagliptin or sitagliptin would be the most appropriate therapies to prescribe for Larry. The other DPP-4 inhibitors (saxagliptin and alogliptin) are contraindicated for patients with heart failure (HF), and the SGLT2 inhibitors (canagliflozin and empagliflozin) are contraindicated based on Larry s renal impairment. The glucagon-like peptide-1 (GLP-1) receptor agonists would be potentially useful; however, the patient has a strong preference for an oral vs injectable medication. SELECTING THE APPROPRIATE ANTIHYPERGLYCEMIC TREATMENT After selecting the T2D drug class that meets the unique needs and goals of a particular patient, the attributes of medications within the drug class must be considered to ascertain the optimal therapy for the patient. [1] As discussed earlier, it is reasonable to decrease the dose of metformin and add a DPP-4 inhibitor, given that these antihyperglycemic agents tend to be well tolerated by patients. In addition, avoiding hypoglycemia is a key treatment goal for all patients but particularly for the elderly. There are 4 DPP-4 inhibitors that are commercially used in the United States (Table 4). With the exception of linagliptin, these agents are excreted renally and, thus require dose adjustments in the setting of moderate or severe renal dysfunction. [10-13] Pg.10

11 Table 4. FDA-Approved DPP-4 Inhibitors in Commercial Use in the United States [10-13] Sitagliptin Saxagliptin Linagliptin Alogliptin FDA approval Dosage forms/ strengths Recommended dosing Tablets/100, 50, and 25 mg Tablets/5 and 2.5 mg Tablet/5 mg Tablets/25, 12.5, and 6.25 mg 100 mg once daily 2.5 mg or 5 mg once daily 5 mg once daily 25 mg once daily Elimination route Renal (~80%) Renal (12%-29% as parent, >20% to ~50% as metabolite) Dose adjustment needed 50 mg once daily for CrCl 30 to <50 ml/min 25 mg once daily for CrCl <30 ml/min 2.5 mg once daily for CrCl <50 ml/min Biliary (>70%) Renal (>70%) Half-life ~12 h ~3 h 12 h 21 h Peak levels 1-4 h after ingestion 2-4 h after ingestion 1.5 h after ingestion NA 12.5 mg once daily for CrCl 30 to <60 ml/min 6.25 mg once daily for CrCl 15 to <30 ml/min 1-2 h after ingestion CrCl = creatinine clearance; DPP-4 = dipeptidyl peptidase-4; FDA = US Food and Drug Administration; NA = not applicable. Based on renal function alone, the case patient could be prescribed linagliptin 5 mg or a reduced dose of sitagliptin (50 mg, instead of 100 mg once daily). [10,12] Dose adjustment of saxagliptin (to 2.5 mg from 5 mg) or alogliptin (to 12.5 mg from 25 mg) would be appropriate for patients with moderate renal impairment who do not have other contraindications for these agents. [11,13] Cardiovascular Outcomes Trials for DPP-4 Inhibitors The selection of a DPP-4 inhibitor should reflect the patient s comorbidities and clinical status, among other factors. For the case patient, the effect on cardiovascular (CV) risk and mortality is a consideration, as Larry has HF, hypertension, and atrial fibrillation. Results from clinical trials evaluating the effect on CV risk for 3 of the 4 commercially used DPP-4 inhibitors in the United States have been published. In 2008, the US Food and Drug Administration (FDA) mandated large cardiovascular outcomes trials (CVOTs) for use of antihyperglycemic treatments in high-risk populations, such as the elderly. [14] The baseline characteristics of the patients enrolled in the DPP-4 inhibitor trials differ, which complicates comparison of CV outcomes among the agents. That said, SAVOR- TIMI53 (saxagliptin), EXAMINE (alogliptin), and TECOS (sitagliptin) demonstrated noninferiority to placebo in terms of CV death, myocardial infarction (MI), or stroke. [15-17] Still, SAVOR-TIMI 53, which enrolled 16,492 patients with T2D and a history of or risk for CV events, showed that significantly more patients taking saxagliptin than placebo were hospitalized for HF during a median follow-up of 2.1 years (P =.007). [15] A subsequent analysis found that treatment with saxagliptin compared with placebo resulted in a significantly higher HF hospitalization rate at 12 months, at 1.9% and 1.3%, respectively (P =.002). [18] Multivariate analysis revealed that prior HF, chronic kidney disease, and elevated natriuretic peptide levels were associated with increased risk for HF hospitalization. The EXAMINE trial, which assessed the CV safety of alogliptin in patients with T2D and acute coronary syndrome, showed a nonsignificant trend toward HF hospitalization for patients taking alogliptin (3.9%) compared with control participants (3.3%). [17,19] After an advisory panel reviewed the SAVOR-TIMI 53 and EXAMINE clinical data, the FDA issued a drug safety communication with a warning against using saxagliptin or alogliptin in patients with T2D who already have heart or kidney disease. [20] There was no HF signal for sitagliptin in the TECOS study (N=14,671). The HF hospitalization rate was not significantly different between the sitagliptin and placebo arms (3.1% for both groups) at a median follow-up of 3 years. [16] The CVOT for linagliptin, CARMELINA, is expected to enroll 8000 patients with T2D; estimated completion is January [21] Thus, neither saxagliptin nor alogliptin would be appropriate for the case patient. It would be at the clinician s discretion to prescribe a reduced dose of sitagliptin--to account for renal impairment--or linagliptin. Pg.11

12 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME Question Introduction: Larry returns for a follow-up visit at 3 months. His HbA 1c has improved to 7.8%, with a fasting blood glucose of 127 to 143 mg/dl. Larry seems to be tolerating the DPP-4 inhibitor. Question 5. What would be the appropriate course of action for Larry s antihyperglycemic treatment? x Continue the current treatment regimen Add glipizide 5 mg to the treatment regimen Add pioglitazone 15 mg Add insulin glargine U-100 or U-300 Answer Explanation: As the patient is close to the goal HbA 1c of between 7% and 8%, adding a short-acting sulfonylurea might be adequate to get to the target. Glipizide is the safest sulfonylurea in patients with chronic kidney disease because of its short half-life. Alternatives are to reinforce diet and exercise or to add low-dose basal insulin. Insulin glargine may be needed if this patient s HbA 1c increases to greater than 8.0% in the future. Either U-100 or U-300 would be appropriate. Insulin glargine U-300 has a longer half-life and may be appropriate for patients needing once-daily dosing with a pen, whether low or high doses are needed. The thiazolidinedione pioglitazone is not appropriate, as it is associated with an increased risk for HF as well as bone fracture in elderly patients. TREATMENT MODIFICATION The decision to intensify treatment for elderly patients is complicated by conflicting goals: minimize the risk for microvascular complications and avoid the risk for hypoglycemia. For some elderly patients with multiple comorbidities, an HbA 1c of less than 8.0% may be acceptable. Depending on the patient s status, complications, and goals, it may be preferable to add another antihyperglycemic agent to the treatment regimen. [1] When the patient has renal dysfunction and a history of drug-related GI intolerance, the treatment options are limited, particularly in the setting of existing cardiovascular disease (CVD). Figure 1. AGi = α-glucosidase inhibitor; DPP-4 = dipeptidyl peptidase-4; GLN = glutamine; GLP-1 = glucagon-like peptide-1 receptor agonist; HbA 1c = glycated hemoglobin; MET = metformin; QR = quick release; RA = receptor agonist; SGLT2 = sodium-glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione. Pg.12

13 Newer formulations of basal insulin, such as glargine U-300 and degludec U-100/U-200, have more stable pharmacodynamics and pharmacokinetics than detemir insulin and glargine U-100. These newer formulations also have demonstrated a lower incidence of severe hypoglycemia than older basal insulin analogs. [1] Avoiding hypoglycemia is critical in patients with T2D and heart disease because of the propensity for hypoglycemia to cause cardiac arrhythmia. [22] CASE CONCLUSION Management of T2D in the elderly, or in patients with multiple comorbidities is part art, part science. This patient is receiving the DPP-4 inhibitor and glipizide 5 mg. His HbA 1c is now 7.5% without hypoglycemia. One of the key points to this case is that his therapy may need to be reconsidered if his kidney function changes (stop metformin), if glipizide causes hypoglycemia, or if his HbA 1c increases. As kidney function worsens, an excellent regimen is linagliptin (or sitagliptin) and basal insulin. Pg.13

14 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME CASE 2: PATIENT HISTORY Jeff, a 52-year-old worker in a machine shop, was recently diagnosed with T2D. He has hypertension, coronary artery disease, and obstructive sleep apnea (OSA). His family history includes heart disease. He is taking a diuretic and a statin. Jeff is obese (body mass index = 36 kg/m 2 ) but is adamant about losing weight. He works long shifts but cannot take frequent breaks. Recent lab work shows an HbA 1c of 8.3% and fasting blood glucose of 159 to 185 mg/dl. He is a former smoker and consumes 3 to 4 beers each week. Question 6. In discussing treatment with Jeff, what is the most appropriate first step? x Address lifestyle modification (diet, exercise, etc) and the need for pharmacotherapy Ask about his moods and sleep cycle Provide an overview of antihyperglycemic treatments Discuss bariatric surgery Answer Explanation: Although all of the answer choices may be appropriate in a discussion with a patient who has elevated HbA 1c and a body mass index = 35 kg/m 2 or higher, lifestyle modification is the cornerstone of T2D management and should be considered the first step in treatment discussions. Still, because T2D is a progressive disease, many patients need pharmacotherapy in addition to lifestyle modifications and should be educated accordingly. LIFESTYLE OPTIMIZATION IS A CORNERSTONE OF T2D MANAGEMENT For all patients with T2D, lifestyle optimization is a lifelong goal that needs to be reinforced frequently. It encompasses several aspects, including nutrition, exercise, sleep quality, behavioral support, and smoking cessation (if applicable). [1] Clinical trials have shown that calorie restriction is typically the primary method for weight loss. Patients who are overweight or obese could see multiple health benefits--including significant improvement in HbA 1c, systolic and diastolic blood pressure, high-density lipoprotein cholesterol (HDL-C), and triglycerides--by losing just 5% to 10% of body weight. [24] In addition to calorie intake restriction, the AACE/ACE guidelines recommend a diet largely focused on vegetables and polyunsaturated fatty acids, such as those found in fatty fish (eg, salmon, mackerel, and trout) and monounsaturated fats (eg, olive oil). Trans fats should be avoided. [1] Many patients have inadequate knowledge of nutrition, including foods that have a high glycemic index, and thus need counseling as to which foods promote (or adversely affect) metabolic health. Patients also may not realize that daily intake of carbohydrates should be consistent. Overweight and obese patients may benefit from structured weight-loss counseling (weekly or monthly sessions) or meal replacement plans. [1] With regard to physical activity, the AACE/ACE guidelines recommend moderate intensity exercise, such as brisk walking, for at least 150 minutes each week. Exercise programs should also include strength training. Wearable technologies and apps can motivate patients to achieve exercise goals. Some patients may need the routine of a structured exercise program. [1] Pg.14

15 Sleep duration and quality should also be considered in lifestyle optimization plans, as sleep deprivation exacerbates insulin resistance and has a negative effect on glucose levels, blood pressure, and lipids. The AACE/ACE recommends nightly sleep of 7 hours for all patients with T2D. Patients complaining of daytime sleepiness should be referred to a sleep specialist for evaluation for OSA. [1] For patients with established OSA, frequent follow-up with regard to use of continuous positive airway pressure devices and sleep masks is needed to reinforce adherence. Lifestyle optimization also includes an assessment of a patient s psychological well-being, as many patients with T2D (with and without obesity) suffer from anxiety and depression. Participation in a community support group helps many patients. The AACE/ ACE recommends referral to a mental healthcare provider for patients with mood disorders. [1] Smoking cessation, if applicable, should be addressed. The AACE/ACE has a complications-centric approach to obesity. Patients with a body mass index of 35 kg/m 2 or higher who are experiencing 1 or more obesity-related complication, such as T2D and hypertension, may be considered for bariatric surgery. [25] Question Introduction: Jeff is educated on the importance of lifestyle modifications, including diet, weight loss, and exercise. Question 7. In addition to lifestyle modifications, what is the optimal antihyperglycemic treatment regimen for Jeff? x Metformin 2000 mg daily Metformin plus an SGLT2 inhibitor Metformin plus a GLP-1 RA Insulin glargine U-100 Answer Explanation: Dual therapy is indicated to address Jeff s HbA 1c of 8.3%. Metformin plus a GLP-1 RA is best suited to reduce Jeff s HbA 1c to less than 6.5%, assist in weight loss, help reduce his cardiovascular risk, and accommodate the demands of his work environment. CUSTOMIZING COMBINATION THERAPY FOR OBESE PATIENTS WITH T2D Patients with an HbA 1c of 7.5% or higher should be placed on dual therapy. [1] (Insulin therapy is not typically recommended unless HbA 1c is greater than 9.0%.) Similar to the American Diabetes Association (ADA), the AACE/ACE guidelines recommend metformin as the first-line therapy for patients with T2D. Unlike the ADA, the AACE/ACE suggests hierarchy of usage of T2D treatments as the add-on to metformin (or other first-line agent): GLP-1 RAs, SGLT2 inhibitors, DPP-4 inhibitors, thiazolidinediones, and basal insulin, followed by less-used antihyperglycemic medications (eg, colesevelam). [1] Although this is the suggested hierarchy of use, combination therapy must be individualized, reflecting the efficacy, effect on weight, hypoglycemia risk, other AEs, and CV safety, among other factors. [1] Both GLP-1 RAs and SGLT2 inhibitors have demonstrated improvements in both total body weight and blood pressure. [1] GLP-1 RAs, incretin-based injectable therapies, stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. This drug class induces satiety through a delay in gastric emptying. Clinical studies evaluating GLP-1 RAs either as monotherapy or as add-on to metformin have shown an average HbA 1c reduction of 0.7% to 1.7%. [26] The incidence of hypoglycemia is low. [1] Weight loss averages 2 kg to 5 kg. [26] The degree of weight loss is dose-dependent; however, it should be noted that the incidence of drug-related GI complaints (eg, nausea, vomiting, etc) is also dose dependent. [26] Early reports of acute pancreatitis for first-generation GLP-1 RAs led to alarm regarding their use in patients with T2D who already have heightened risk for pancreatitis compared with individuals without T2D. Subsequent studies suggest that the drug class is not associated with an increased risk for pancreatitis compared with control. [26] Still, the AACE/ACE guidelines recommend that GLP-1 RAs should be used cautiously--if at all--in patients with a history of pancreatitis. [1] If acute pancreatitis develops, the GLP-1 RA should be discontinued. [1] In addition, some studies have shown that certain GLP-1 RAs elevate the heart rate. [26] Pg.15

16 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME SGLT2 inhibitors, the newest antihyperglycemic drug class, have a novel mechanism of action. Instead of inhibiting hormones and enzymes involved in the digestive process, this new drug class targets the SGLT2 protein, which is located on the proximal renal tubules. By inhibiting SGLT2, the renal threshold for glucose is reduced, renal glucose reabsorption is blocked, and glycosuria is increased. The change in the renal glucose threshold is likely behind the low rate of hypoglycemia seen with SGLT2 inhibitors. The mechanism of action is insulin-independent, which makes SGLT2 inhibitors complementary to other antihyperglycemic treatments. [27] Average HbA 1c reduction afforded by SGLT2 inhibitors when used as monotherapy or as an add-on to metformin is 0.32% to 1.17%. [26] As with other T2D therapies, greater HbA 1c reduction is observed with higher baseline levels. [26] Average weight loss recorded in clinical trials was 1.5 kg to 3.0 kg compared with placebo [26] ; however, weight loss tends to plateau, and some patients regain lost weight. [27] Adverse events include polyuria, genitourinary infections, hypotension, bone fractures, and diabetic ketoacidosis. [26] With regard to the latter, the AACE and ACE convened a conference in October 2015 to review the clinical data. An expert consensus statement was issued noting that the incidence of diabetic ketoacidosis to be infrequent, requiring no change in recommendations. [28] Based on the aforementioned efficacy and safety profiles, a GLP-1 RA may be a more appropriate add-on therapy for the case patient, given his HbA 1c of 8.3% and the greater glycemic index reduction afforded by GLP-1 RAs. When considering certain attributes of SGLT2 inhibitors (increased urination and weight-loss plateau, which might be problematic for the patient), the treatment decision leans further toward metformin/glp-1 RA combination therapy. CVOTs: Spotlight on LEADER and EMPA-REG Most CVOTs for GLP-1 RAs and SGLT2 inhibitors are still in progress. To date, 4 have been completed, as shown in Table 5. Table 5. Completed CVOTs for GLP-1 RAs and SGLT2 Inhibitors [13,29-32] Trial Drug/Comparator Patients, N Average Follow-Up, y Primary Endpoint Endpoint vs Comparator LEADER [29] Liraglutide/placebo CV death, MI, or stroke P <.001 for noninferiority; P =.01 for superiority ELIXA [30] Pg.16 Lixisenatide/ placebo SUSTAIN-6 [31] Semaglutide 0.5 mg or 1.0 mg*/placebo EMPA-REG Empagliflozin 10 OUTCOME [32] mg or 25 mg/placebo CV death, MI, UA, or stroke P <.001 for noninferiority; did not demonstrate superiority to placebo CV death, MI, or stroke P <.001 for noninferiority; P =.02 for superiority CV death, MI, or stroke P <.001 for noninferiority; P =.04 for superiority CV = cardiovascular; CVOT = cardiovascular outcomes trial; FDA = US Food and Drug Administration; MI = myocardial infarction; UA = unstable angina. *Has not yet received FDA approval. EMPA-REG OUTCOME, which assessed the CV safety of SGLT inhibitor empagliflozin, was the first antihyperglycemic CVOT to demonstrate superiority. The trial enrolled 7020 patients with T2D, established CVD, and high risk for CV events. The mean age was 63 years, and the majority of participants (57%) had T2D for 10 years or more. All patients were on background antihyperglycemic therapy. Nearly 75% of individuals in each cohort (empagliflozin 10 mg, empagliflozin 25 mg, placebo) were taking metformin; approximately 48% were on insulin. Still, average baseline HbA 1c was greater than 8.0% for all groups. At a median follow-up of 3.1 years, significantly fewer patients in the combined empagliflozin groups had a primary event (CV death, MI, or stroke) than control participants, at 10.5% and 12.1%, respectively (P =.04). Of note, empagliflozin had a relative risk reduction of 38% for CV death compared with placebo (3.7% for the pooled empagliflozin cohort at 3.7% compared with 5.9% for placebo; P <.001). There were no differences between the groups in terms of MI or stroke. Empagliflozin also had a significantly lower HF hospitalization rate, a secondary endpoint, at 2.7% compared with 4.1% for control participants (P =.002). [32] EMPA-REG OUTCOME results were included in updated ADA guidelines. [1,6] In December 2017, the FDA expanded labeling on empagliflozin for use in patients with T2D and established CVD to reduce the risk for CV death. [33]

17 LEADER randomized 9340 patients with T2D with high CV risk and with or without established CVD to receive liraglutide or placebo to standard antihyperglycemic therapy. The mean age was 64 years, with an average T2D duration of nearly 13 years. More than 80% of the liraglutide and control groups had established CVD: Approximately 30% had a prior MI, and nearly 40% had had a revascularization. More than 15% of both groups had a history of stroke or transient ischemic attack. Similar to EMPA-REG OUTCOME, the majority of patients ( 75%) in both arms were taking metformin; more than 40% were on insulin. Baseline HbA 1c averaged 8.7%. At a mean of 3.8 years, the number of patients in the liraglutide arm had significantly fewer CV events (CV death, nonfatal MI, or nonfatal stroke) than did control participants (13.0% vs 14.9%, respectively) (P =.01), equating to a hazard ratio of Liraglutide also had lower, albeit nonsignificant, rates for nonfatal MI or stroke. Liraglutide s relative safety benefit was driven by significantly fewer CV deaths than control at 4.7% vs. 6.0%, respectively (P =.007). [29] Both EMPA-REG OUTCOME and LEADER showed some improvement in blood pressure parameters for patients taking empagliflozin and liraglutide, respectively. [29,33] At baseline, the mean blood pressure for patients taking empagliflozin was 135.3/76.6 mm Hg. At study end, blood pressure averaged 133/75 mm Hg for patients in the investigative arm. [33] Patients in the liraglutide cohort had similar baseline blood pressure at a mean of 135.9/77.2 mm Hg. Systolic blood pressure was lowered by 1.2 mm Hg, with a reduction of 0.6 mm Hg for diastolic blood pressure. [29] Regarding lipid levels, empagliflozin reduced low-density lipoprotein cholesterol (LDL-C) but raised HDL-C. [33] Data on lipid levels were not published for LEADER. [29] Patients in the investigative arms of both trials lowered body weight by approximately 2 kg. [29,33] EMPA-REG OUTCOME and LEADER do not suggest a clear advantage for empagliflozin or liraglutide. The time to benefit was observed somewhat earlier in EMPA-REG OUTCOME than in LEADER [33] ; however, it is not clear whether that reflects a treatment benefit or different patient populations (100% established CVD in EMPA-REG OUTCOME vs ~80% in LEADER) or another effect. [29] The principal investigators of LEADER hypothesized that empagliflozin s CV benefit may be more closely linked to hemodynamic changes, and liraglutide s CV benefit may be derived from altering the progression of atherosclerosis. [29] Based on the totality of the available scientific evidence, liraglutide would seem the optimal add-on to metformin for the case patient based on likely HbA 1c reduction, weight loss, CV risk reduction, and accommodation of the patient s work schedule, which does not allow for frequent breaks. Other Completed CVOTs: ELIXA and SUSTAIN-6 ELIXA randomly assigned 6068 patients with T2D and acute coronary syndrome to lixisenatide or placebo with standard therapy. At a mean baseline age of ~60 years, the patients were slightly younger than patients in EMPA-REG OUTCOME and LEADER were. The baseline average HbA 1c was also lower, at 7.6% to 7.7%, with a mean duration of T2D of about 9 years. At a median follow-up of 25 months, lixisenatide demonstrated noninferiority but not superiority to placebo on a composite of CV death, MI, stroke, or hospitalization for unstable angina. There were no significant differences between the 2 groups on CV death, at 5.1% for lixisenatide and 5.2% for control. [30] SUSTAIN-6 demonstrated superiority for semaglutide* compared with placebo on a composite endpoint of CV death, MI, or stroke. The trial enrolled 3297 patients with T2D. The average age approached 65 years, with a mean duration of T2D of about 14 years. At baseline, HbA 1c averaged 8.7%. The majority of participants (83.0%) had established CVD, kidney disease, or both. Although semaglutide demonstrated superiority to placebo on the primary endpoint, there were no significant differences between the investigative and control arms with regard to CV death. Semaglutide s CV safety benefit was driven by a significantly lower rate of nonfatal stroke compared with placebo. [31] Semaglutide is undergoing regulatory review in the United States and is not currently approved for use in patients with T2D. Question 8. After initiation of a GLP-1 RA, what is the most important challenge to help this patient maximize the benefit of the therapy? x Dose escalation Drug-to-drug interactions Fasting blood glucose Acute kidney injury Answer Explanation: Dose escalation to minimize the incidence of adverse events, such as nausea and vomiting, can be challenging. Pg.17

18 Integrating New Type 2 Diabetes Algorithms into Clinical Practice: Applying AACE Guidelines to Complex Patients with Diabetes CME PRACTICAL INSIGHT INTO GLP-1 RA USE Adverse events, such a nausea and vomiting, may be seen early in treatment with GLP-1 RAs if high doses are initially prescribed and can be minimized by careful dose escalation. [34] This is particularly important, as most patients will not tolerate vomiting for very long. For instance, it is recommended to initiate liraglutide at 0.6 mg daily for 1 week before increasing the dose to 1.2 mg daily or 1.8 mg daily. [35] (The latter may be needed for an obese patient such as Jeff. In addition to glycemic reduction, higher doses of liraglutide should lead to a greater reduction in body weight but at the risk for increased AEs.) For lixisenatide, patients start on 10-μg injections before their first meal for 14 days, after which time the dose increased to 20 μg daily. [36] Lixisenatide is also available in a prefilled pen device in combination with insulin glargine, a basal insulin. [37] Once-weekly formulations have differing titration schedules. The longer-acting GLP-1 RAs may take several weeks to achieve steady concentrations, which physicians and patients need to understand. [34] In general, GLP-1 RAs do not have significant drug-drug interactions although the delay in gastric emptying may affect the absorption of some oral medications. Both shorter- and longer-acting GLP-1 RAs lower fasting blood glucose levels, however longer-acting agents (as well as liraglutide) have a greater effect on fasting plasma levels compared with shorter-acting agents. While there have been some reports of acute kidney injury with certain GLP-1 RAs (liraglutide, dulaglutide, and exenatide which is excreted renally), overall acute kidney injury is very uncommon. Patients should maintain hydration when taking metformin, GLP-1 RAs and SGLT2 inhibitors, and hold the drugs for medical procedures or illness that involves vomiting. Question 9. According to Association of Clinical Endocrinologists/American College of Endocrinology guidelines for T2D management, what nonglycemic goal should be set for Jeff? x Weight loss of 5 kg to 10 kg Low-density lipoprotein cholesterol <70 mg/dl Triglycerides <100 mg/dl Blood pressure <140/80 mm Hg Answer Explanation: Based on Jeff s risk profile for atherosclerotic cardiovascular disease, his target low-density lipoprotein cholesterol should be <70 mg/dl. CV RISK MODIFICATION Patients with T2D have a significantly higher risk for atherosclerotic cardiovascular disease (ASCVD) than patients without T2D. [1] As a result, the AACE/ACE guidelines recommend early intensive management of dyslipidemia, with varying goals based on the degree of risk (high, very high extreme). [1] A patient with very high risk, such as Jeff, should be set lipid goals of LDL-C <70 mg/dl and non-hdl-c of <100 mg/dl, as shown in Table 5. Triglyceride targets should be <150 mg/dl regardless of ASCVD risk categorization. [1] The AACE/ACE guidelines support a blood pressure goal of <130/80 mm Hg as appropriate for most patients with T2D. There is a preference for use of either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker for blood pressure management, as these agents may slow progression of diabetes-related nephropathy or retinopathy. [1] Weight loss of 5% to 10% of total body weight can have clinically relevant effects. [1] Pg.18