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Home , Dasiglucagon, Dulaglutide, NPH insulin, Prediabetes

4/15/2021

Disclosure • I, or an immediate family member, including spouse or partner, have no financial relationship(s) relevant to the content of this CPE activity to disclose. Update 2021

Brooke Hudspeth, PharmD, CDCES, MLDE Associate Dean/Chief Practice Officer University of Kentucky College of Pharmacy

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Objectives 1: Which of the following is true regarding monitoring recommendations in patients with diabetes? • Summarize the 2021 updates to the American Diabetes Association (ADA) Standards of Medical Care in Diabetes and other guidelines. A. With lower eGFR levels, the accuracy of A1c • Discuss findings from recent clinical trials that may influence measurements increases. and care. B. Continuous Monitoring (CGM) has • Identify new and emerging trends for management of type 2 recently been FDA-approved for inpatient use. diabetes. C. A1c is currently the only measure to guide glucose management, and CGM metrics should not be used in a patient’s diabetes management plan. D. Overreliance on A1c levels should be avoided in the very complex older adult. 3 4 3 4

3: The VERTIS trial showed that: 2: Diabetes education is recommended:

A. At diagnosis A. is non-inferior for CV outcomes, but not superior to B. When there are transitions in life and/or care placebo C. With the development of complicating factors that influence self- B. Patients with LDL at goal but TG elevated, use of Icosapent Ethyl management should be considered D. All of the above C. Oral is non-inferior for CV outcomes D. Early combination therapy may have benefits for newly- diagnosed T2DM patients.

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4: Which of the following statements are true regarding cardiovascular management in patients 5: In patients requiring injectable therapy: with diabetes? A. All patients requiring injectable therapy should begin with basal A. Lipid therapy recommendations do not differ . between primary or secondary prevention and B. Consider GLP-1 RA in most patients prior to insulin. ASCVD risk C. Little emphasis should be placed on as it has no B. The ADA standards of care suggest that GLP-1 impact on glycemic control. receptor agonists and SGLT2 inhibitors should be considered for patients when atherosclerotic D. There is one best approach to insulin treatment in patients with cardiovascular (ASCVD), heart failure, or diabetes. chronic predominates, but only when A1C > 10%. C. Setting BP target is based on 10-year ASCVD risk D. CVOTs are optional for new therapies for T2DM.

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ADA Standards of Care

• American Diabetes Association: Standards of Medical Care in Diabetes 2021 • www.diabetes.org Standards of Care • Diabetes Care 2021, Volume 44, Supplement 1 • “Living” document 2021 Revisions

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Social Determinants of Health A Silent Risk • 1.5 Assess food insecurity, housing insecurity/homelessness, 34.2 million Americans financial barriers, and social capital/social community support and with diabetes apply that information to treatment decisions.

• “Cost-related nonadherence” 88 million Americans with

9 out of 10 adults with prediabetes are unaware they have it

Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2020. Atlanta, GA; US Department of Health and Human Services, Centers for Disease Control and Prevention, 2020https://www.cdc.gov/diabetes/data/statisticsreport/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fdiabetes% 2Fdata%2Fstatistics%2Fstatistics-report.html

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Overview of the National Diabetes Prevention Program

The core of the National Diabetes Prevention Program (National Denise 1 DPP) is a CDC-recognized, year-long lifestyle change program that offers participants: • Denise is a 59 year old white female with T2DM, HTN, HLD and PMH of an MI (2017) • : • ER 1000 mg BID • Amlodipine 10 mg daily • Atorvastatin 40 mg daily • Lisinopril 10 mg daily To successfully implement these lifestyle change programs, the National 2 DPP relies upon a variety of public-private partnerships including: • Walks ~3-4 times/week and tries to “eat healthy” community organizations, private insurers, employers, health care • Social history: + tobacco use – 1 ppd x 25 years (Pt has recently switched to e-cigarette use organizations, faith-based organizations, and government agencies. in an “attempt to quit ”) Together, these organizations work to: • Has insurance through her employer • Labs • A1C: 7.9% • BP: 124/76 • SCr: 1.0; eGFR >60 • Weight: 196 lbs; BMI: 34 kg/m2 • TC = 135; HDL = 39; TG = 175; LDL = 61

http://www.cdc.gov/diabetes/prevention/pdf/ndpp_infographic.pdf 14 13 14

Facilitating Behavior Change and Well- being to Improve Health Outcomes Individualization is Key

Diabetes Tobacco Education Cessation

Physical Nutrition Activty Therapy

Psychosocial Diabetes Issues Distress

Diabetes Care 2021;44(Suppl. 1):S53-S72. This Photo by Unknown Author is licensed under CC BY-NC-ND 15 16 15 16

Diabetes Education

Annually and/or not At Diagnosis meeting treatment targets

Development of Transitions in complicating life and/or factors that care influence self- management

18 Diabetes Care 2021;44(Suppl. 1): Diabetes Care 2020;43(Suppl. 1) 17 18

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Diabetes Care 2020;43(Suppl. 1) Diabetes Care 2021;44(Suppl. 1): 20 19 20

HBD1 ASCVD, HF, CKD

Diabetes Care 2021;44(Suppl. 1): 21 Diabetes Care 2020;43(Suppl. 1):S103 22 21 22

ASCVD, HF, CKD Hypoglycemia

Diabetes Care 2021;44(Suppl. 1): Diabetes Care 2021;44(Suppl. 1):

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HBD1 Hudspeth, Brooke D., 3/28/2021 4/15/2021

Weight Loss Cost GLP-1s

Semaglutide (injectable)

Liraglutide

Dulaglutide

Exenatide

Lixisentatine

25 Diabetes Care 2021;44(Suppl. 1). 26 Diabetes Care 2021;44(Suppl. 1): 25 26

VERIFY Trial Oral Semaglutide • Newly diagnosed with T2DM • Followed for 5 years Mechanism Dosage • Baseline A1C: 6.5-7.5% Administration • Metformin + placebo compared to Metformin + DPP-4i () • Initial combination of metformin with vildagliptin resulted in slower GLP-1 Rapidly Degraded 3 mg daily x 30 days Empty Stomach with ≤ by gastric enzymes THEN 4oz water decline of glycemic control Co-formulated with SNAC 7 mg daily (14 mg daily (sodium N-[8 (2- max dose) Discontinue in women at hydroxybenzoyl) amino] least 2 months before caprylate Allows for absorption of oral semaglutide in stomach No significant drug-drug Takeaway: Early combination therapy interactions may have benefits for newly-diagnosed

T2DM patients. Rybelsus package insert: https://www.novo-pi.com/rybelsus.pdf. 27 Matthews DR et al. Lancet. 2019 Oct 26;394(10208):1519-1529. 28 27 28

VERTIS CVOT Pioneer 6 Trial • Ertugliflozin (5 mg or 15 mg) compared to placebo • Oral semaglutide compared to placebo • ASCVD • Patients with high CV risk • Mean A1C 8.2% • Median A1C 8.2% • Outcomes • 3-point MACE outcomes • Primary: non-inferiority of ertugliflozin to placebo for MACE • CV • Secondary: composite of death from CV cause or HF hospitalization • Nonfatal MI • Nonfatal Stroke Takeaway: Ertugliflozin non-inferior for CV outcomes, but not superior to Takeaway: Oral semaglutide non-inferior placebo for CV outcomes (but not superior)

Husain M, et al. N Engl J Med. 2019; 381:841-851. N Engl J Med. 2020;383(15):1425–1435. 29 29 30

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REWIND Trial and Risk Management • 1.5 mg vs. placebo • ASCVD or high risk Primary Prevention Secondary Prevention • 40-75: Moderate-intensity statin + • All ages: High-intensity statin + • Median A1C 7.2% lifestyle lifestyle • 20-39: May be reasonable to • Very high risk patients and LDL ≥ • 3-Point MACE Outcomes initiate statin therapy in addition to 70 mg/dL and on maximally • CV Death lifestyle if other ASCVD risks tolerated statin: consider adding present ezetimibe or PCSK9 inhibitor • Nonfatal MI • 50-70 at higher risk: reasonable to • Nonfatal Stroke use high-intensity statin • 10-yr ASCVD risk ≥ 20%: reasonable to add ezetimibe to maximally tolerated statin Takeaway: Showed CV benefit in patients

with and without established ASCVD 1.Diabetes Care 2021;44(Suppl. 1):S125 – S150 2.Schwartz GG, Steg PG, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–2107 3. Ray KK, Colhoun HM, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES Gerstein HC, et al. Lancet. 2019;394(10193):121-130. 31 32 31 32

REDUCE-IT • The Reduction of Cardiovascular Events with ODYSSEY Icosapent Ethyl–Intervention Trial • 8,179 adults receiving statin therapy with moderately elevated • Icosapent ethyl 4 g/day (2 g twice daily with food) versus placebo • Primary end point: demonstrated a 25% relative risk reduction (P < 0.001) for the primary end point composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. Takeaway: LDL at goal but TG elevated, consider use of Icosapent Ethyl

Bhatt DL, Steg PG, Miller M, et al.; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22 33 34 33 34

Other CV Considerations CVOT • • DPP-4i • <130/80 mmHg: 10-year ASCVD risk ≥15% • SAVOR-TIMI 53 • EXAMINE • <140/90 mmHg: 10-year ASCVD risk <15% • TECOS • 110-135/85 mmHg: Pregnant Patients with diabetes and preexisting HTN • CARMELINA • ACE inhibitors or angiotensin receptor blockers are recommended first-line therapy for • GLP-1 RA hypertension in people with diabetes and: • ELIXA • coronary disease • LEADER • urinary albumin-to-creatinine ratio ≥300 mg/g creatinine or 30–299 mg/g creatinine • SUSTAIN-6 • Antiplatelet Therapy • EXSCEL • Harmony Outcomes • Primary Prevention: Risk vs. benefit of low-dose aspirin • REWIND • Secondary Prevention: Low-dose aspirin (75-162 mg daily) • SGLT-2i • Aspirin allergy: Clopidogrel (75 mg daily) • EMPA-REG OUTCOME • Long-term treatment with dual antiplatelet therapy should be considered for patients with prior • CANVAS coronary intervention, high ischemic risk, and low bleeding risk to prevent major adverse • DECLARE-TIMI 58 cardiovascular events. • VERTIS • Combination therapy with aspirin plus low-dose rivaroxaban should be considered for patients with stable coronary and/or peripheral artery disease and low bleeding risk to prevent major • MACE (Major Adverse Cardiovascular Event): composite of cardiovascular death, non-fatal MI, non-fatal adverse limb and cardiovascular events. stroke

Diabetes Care 2020;43(Suppl. 1):S111 – S134 Diabetes Care 2021;44(Suppl. 1) 35 36 35 36

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SGLT-2 Inhibitor Considerations CKD • To lower risk of ketoacidosis, SGLT2i should be stopped • KDIGO temporarily prior to scheduled surgery • First line therapy: metformin + SGLT2i • Stop at least 3 days ahead: , , • eGFR <30 do not initiate; d/c in dialysis • Stop at least 4 days ahead: Ertugliflozin • Preferred additional therapy: long acting GLP-1 RA • eGFR <15: DPP4i, insulin, TZD • Glucose Monitoring Considerations • Dialysis and use of erythropoietin-stimulating agents: A1c ↓ • Lower eGFR: A1c innacurate • Goal A1c: <6.5%-<8% (depending on comorbidities) • CGM: useful tool for glycemic assessment

Drug Safety Communication. www.fda.gov

Kidney Int. 2020;98(4S):S1–S115. 37 37 38

Safety Changes: Canagliflozin CREDENCE Trial • Lower limb amputation black box warning removed (remains in warnings and precautions) • Canagliflozin 100 mg vs. placebo • Initiate canagliflozin 100 mg in adults with T2DM and eGFR >30 • ~60% of participants to have eGFR of 30 - <60 ml/min/1.73m2 (with or without albuminuria) • Primary Outcome: ESRD, SCr doubling, CV or renal death • Only continue if eGFR <30 if albuminuria is >300 mg/day unless • Initial dip in eGFR in canagliflozin group, but then less of a steady dialysis is initiated. decline than placebo

Takeaway: Recommend use of SGLT2i in patients with CVD or CKD down to an eGFR of www.fda.gov/media/141533/download 30 ml/min/1.73m2 independent of glucose lowering effect.

Perkovic V, et al. NEJM. 2019;380(24):2295–2306. 40 39 40

Heart Failure • HFrEF (LVEF <45%): SGLT2i with proven heart failure benefits • Primary outcome data for heart failure: dapagliflozin and empagliflozin • Reduction in heart failure outcomes in CVOTs: empagliflozin, canagliflozin, and dapagliflozin Remember Denise

Diabetes Care. 2021;44(Suppl. 1):S111–S124.

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Denise…1 year later Glycemic Targets

• Denise returns to your clinic 1 year later • Medications: • Metformin ER 1000 mg BID • 1.8 mg daily • Amlodipine 10 mg daily • Atorvastatin 40 mg daily • Lisinopril 10 mg daily • Patient had achieved A1C control after the initial therapy changed, but is elevated again at this visit at 7.7%

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Continuous Glucose Monitoring Glycemic Targets • Ambulatory Patients • A1C  Glycemic Assessment • Multiple Daily Injections • Continuous SubQ Insulin Infusions • Other Forms of Insulin Therapy • Clinic Based Monitoring • “Professional CGM” • Inpatient Use • Not FDA approved for inpatient use • COVID-19 Considerations

Diabetes Care. 2021;44(Suppl. 1):S211–S220. Diabetes Care. 2021;44(Suppl. 1):S73–S84. 45 46

Potential A1C Limitations Continuous • Hemoglobin variants • Assay Interference • Conditions associated with red blood cell turnover • Ethnicity • Age

Goal A1C <7%

Goal A1C 8%

Every 10% increase in TIR is associated with a decrease in A1C of 0.5-0.8%

Battelino T, et al. Diabetes Care.2019;42:1593-1603. Diabetes Care 2020;43(Suppl. 1) Diabetes Care 2020;43(Suppl. 1):S14–S31 47 48 47 48

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Injectable Therapies

49 Diabetes Care 2020;43(Suppl. 1):S14–S31 49 50

Overbasalization Consider Adjunctive Therapy • Add GLP-1 receptor agonist if not already part of regimen • Assess adequacy of basal insulin dose • Add prandial insulin: 4 units per day or 10% of basal inulin • Clinical signals of overbasalization/need to consider adjunctive therapies • Basal dose > 0.5 unit/kg/day dose. ***If A1c <8.5, consider decreasing basal dose by 4 IU • Elevated bedtime-morning differential (>50 mg/dL) per day or 10% decrease of basal dose • Elevated post-preprandial differential • Hypoglycemia (aware or unaware) • If NPH insulin at bedtime only, consider converting to twice daily • High glucose variability NPH

Diabetes Care. 2021;44(Suppl. 1):S111–S124.

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Hypoglycemia Special Populations • Autoinjector Nasal Glucagon Powder • Older Adults

Baqsimi package insert: http://uspl.lilly.com/baqsimi/baqsimi.html#pi 8. Gvoke package insert: https://www.gvokeglucagon.com/pdf/gvoke-prescribinginformation.pdf 54 53 54

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Older Adults

The Future of Diabetes Management

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Automated Insulin Dosing Agents in Phase III Clinical Trials, FDA-filed, newly approved • Control-IQ • FDA approved for T1DM • GLP-1 RA • Bolus change and basal change based on predicted glucose • Dulaglutide 3.0 mg/4.5 mg: Higher dose for T2DM • Exercise Mode • Tirzepatide: Dual GLP-1 RA and GIP, once-weekly • Efpeglenatide: Once-weekly • Bionic Pancreas System • SGLT-2i • Insulin Only • Empagliflozin: Type 1 DM • Glucagon Only • Insulin • Insulin Icodec • Bihormonal • Delayed onset of T1DM • Teplizumab •

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1: Which of the following is true regarding 2: Diabetes education is recommended: monitoring recommendations in patients with diabetes? A. At diagnosis B. When there are transitions in life and/or care A. With lower eGFR levels, the accuracy of A1c measurements increases. C. With the development of complicating factors that influence self- management B. Continuous Glucose Monitoring (CGM) has recently been FDA-approved for inpatient use. D. All of the above C. A1c is currently the only measure to guide glucose management, and CGM metrics should not be used in a patient’s diabetes management plan. D. Overreliance on A1c levels should be avoided in the very complex older adult. 59 60 59 60

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3: The VERTIS trial showed that: 4: Which of the following statements are true regarding cardiovascular management in patients with diabetes? A. Ertugliflozin is non-inferior for CV outcomes, but not superior to placebo A. Lipid therapy recommendations do not differ B. Patients with LDL at goal but TG elevated, use of Icosapent Ethyl between primary or secondary prevention and should be considered ASCVD risk C. Oral semaglutide is non-inferior for CV outcomes B. The ADA standards of care suggest that GLP-1 receptor agonists and SGLT2 inhibitors should be D. Early combination therapy may have benefits for newly- considered for patients when atherosclerotic diagnosed T2DM patients. cardiovascular disease (ASCVD), heart failure, or chronic kidney disease predominates, but only when A1C > 10%. C. Setting BP target is based on 10-year ASCVD risk D. CVOTs are optional for new therapies for T2DM.

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5: In patients requiring injectable therapy:

A. All patients requiring injectable therapy should begin with basal insulin. B. Consider GLP-1 RA in most patients prior to insulin. C. Little emphasis should be placed on hypoglycemia as it has no Thank You impact on glycemic control. Brooke Hudspeth, PharmD, CDCES D. There is one best approach to insulin treatment in patients with Associate Professor diabetes. University of Kentucky College of Pharmacy [email protected]

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