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Managing Type 2 Diabetes:Moving beyond Metformin andGlipizideTANYA MUNGER DNP, FNP-BC, AP-PMN, CCHP

Disclosures Speakers Bureau for Novo Nordisk Speakers Bureau for Dexcom Presentation will include brand name medications and technology No off label discussions Presentation will include medications in clinical trial

Diabetes Management Goals A1c 6.5%-8%: depending on age, duration of Dx, and co-morbidconditions Reducing CV risk Weight reduction Minimizing hypoglycemia

Limitations of A1c1. May underestimate or overestimate anindividual’s average glucose (example: A1C of7% could represent a range between 123 -185mg/dL)2. Does not indicate the extent or timing ofhypoglycemia or hyperglycemia3. Does not reveal glycemic variability4. Limited utility for insulin dosing decisions5. Unreliable in patients with hemolytic anemia,hemoglobinopathies, or iron deficiency6. Underestimates in those with end stage kidneydisease or during pregnancyNathan DM et al. Diabetes Care. 2008;31(8):1473-1478A1c%mg/dL95% 0-24910240193-28211269217-31412298240-347

Oral Agents and Non InsulinInjectables– Biguanides– Thiazolidinediones– Dopamine-2 agonists– Meglitinides– Bile acid sequestrants– Alpha-glucosidase– GLP-1 receptor agonistsinhibitors– DPP-4 inhibitors– Amylinomimetics– Sulfonylureas– SGLT-2 inhibitors

Biguanides-Metformin (Glucophage) Anticipated A1c reduction: 1-2% Targets insulin resistance Reduces hepatic glucose production and intestinal glucose absorption Fasting and post prandial Hypoglycemic risk: minimal GI side effects-titrate slowly Weight neutral/weight loss

Biguanides-Metformin(Glucophage) Consider discontinuation eGFR 45, absolute discontinuation eGFR 30 Rare risk of lactic acidosis Long term use associated with B12 deficiency due to altered absorption 90% excreted via kidneys Discontinue before iodine contrast imaging, restart after 48 hrs 500-1000 mg BID, max 2550 mg/day (extended release intended for oncedaily use)

Sulfonylurea(Glipizide, Glyburide, Glimepiride) A1c reduction: 1-2% Fasting & Postprandial Increases insulin release from beta cells Hypoglycemic risk: moderate/severe Less effective in elderly or those with long duration of DM dueto failing beta cell function Weight gain

Sulfonylurea DosingGlyburideGlipizide 1.25-20 mg/day qd-BID 2.5-20 mg qd-BID Max Max 20 mg/day Max 40 mg/day or 20 mg/day ER Take with meals 30 min before meals do not crush/chew Extended release preparations areintended for once daily useGlimeperide 1-4 mg/day Max 8 mg/day Take with first main meal

DDP4 Inhibitors(Januvia, Onlyza, Nessina, Tradjenta) Works on hormones in the gut, increasing insulin production Inhibits DPP-4 enzyme in the GI tract that breaks down GLP-1resulting in endogenous GLP-1 Prolonged endogenous GLP-1 action: decrease liver glucoseproduction, enhances insulin & amylin secretion in pancreas Weight neutral A1c lowering: 0.5-0.8% Post prandial benefits Nasopharyngitis, URI

DPP4 Inhibitor DosingSitagliptin (Januvia )Linagliptin (Tradjenta ) 25 Once-daily dosing 5 mgmg, 50 mg, and 100 mg Once-dailydosingSaxagliptin (Onglyza )Alogliptin (Nesina ) 2.5 Once-daily dosing 6.25mg, 12.5mg,25 mgmg and 5 mg Once-dailydosing

Cardiovascular Risk Reduction &Weight Reduction

GLP-1 Receptor Agonists:Exenatide (Bydureon/Byetta), Liraglutide (Victoza),Dulaglutide (Trulicity), Semaglutide (Ozempic,Rybelsus) Ozempic, Trulicity, Rybelsus, Victoza, Byetta, Bydureon Weight reduction CV risk reduction A1c reduction: 1-2% SE: nausea, fullness, bloating, constipation Contraindicated in pts with Hx of MTC and pancreatitis No renal or hepatic dose adjustments

GLP-1 Receptor Agonist Dosing Liraglutide (Victoza ) 0.6 mg, 1.2 mg, & 1.8 mg Once-dailydosing Exenatide (Bydureon ) 2 mg Once-weekly dosing; (Byetta ) 5& 10 mcg/BID (short acting) Semaglutide (Ozempic ) 0.25-1mg Once weekly Semaglutide (Rybelsus ) 3 mg, 7 mg, 14 mg, once daily, oral Dulaglutide (Trulicity ) 0.75mg & 1.5mg, 3 mg, 4.5 mg Onceweekly dosing

Rybelsus (Semaglutide) Oral GLP1 with special coating Once daily No more than 4 ounces of water No food, beverages, or medications for 30 mins 3 mg, 7 mg, 14 mg No adjustments for age, hepatic or renal disease

Wegovy (Semaglutide) GLP-1 indicated for weight loss Auto injector pens Once weekly dosing Dosing: 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, 2.4 mg Titrate upward to 2.4 mg weekly

Sodium Glucose Transport Inhibitors(SGLT2) Farxiga, Jardiance, Steglatro, Invokanna Once daily oral Removes glucose from blood stream via kidneys/urine A1c Reduction: 1% BP lowering Weight reduction CV risk reduction Slows progression of CKD (Farxiga) Decreases readmission in CHF (Farxiga)

SGLT2 Inhibitor DosingDapagliflozin Farxiga 5-10 mg once dailyEmpagliflozin Jardiance 10-25 mg once dailyRisk of UTI and yeast infection in groinDrink plenty of waterKeep groin area clean and dryInvokana-increased amputation riskCanagliflozin Invokana 100-300 mg once dailyErtugliflozin Steglatro 5-15 mg once daily

Farxiga (Dapagliflozin) FDA labeling for reducing CV risk, progression of CKD (pts with DMand without) and hospital admissions fro HF GFR for glucose management: 45 GFR for reducing progression of CKD: 25 Once on the medication can remain on until dialysis Voucher for 30 days free

Jardiance (Empagliflozin) FDA indicated to reduce CV risk and hospital admissions for HF Kidney data available, CKD labeling in the future GFR for glucose lowering: 30 GFR for HF: 20

Voucher Programs Trulicity Ozempic Farxiga Bydureon Vouchers are for a free 30 day supply Jardiance: 14 day free voucher Not a coupon or co-pay card Pharmaceutical rep needs to have contact with provider or evenclinic manager

History of Insulin Starvation diets 400-500 calories daily First insulin bovine-many allergies First injection Jan 1922 Diabetes no longer a deathsentence, now a manageablechronic condition

History of Insulin First insulin U-20 the U-50 Biosynthetic commerciallyavailable 1980’s Lantus/Levemir year 2000

Insulin TherapySpectrum of OptionsConventional ogy

Indications for Insulin Therapy inType 2 Diabetes Significant hyperglycemia at dx Hyperglycemia despite being on effective doses of orals Intolerance of orals due to side effects Renal or hepatic disease Surgery, pregnancy, hospitalization (acute injury, infection, stress) Unable to afford oral medications

Starting Basal Insulin Safe to start 10 units once daily (AM or PM) Titrate upward by 2 units daily until FBS is at 150 Can increase by 5-10 units weekly as needed Once pt reaches 50-60 units daily consider meal time coverage

Titration of Insulin Titrate upwards by 3 units every 2-3 days until FBS at goal FBS 180: add 6 units basal (20% TDD) FBS 141-180 add 4units basal (10% TDD) FBS 100-120 add 1 unit (1 unit) FBS 80 or less subtract 2 units (10-20%)

Meal Time Insulin May consider a GLP1 first Discontinue sulfonylurea to avoid hypoglycemia Continue basal insulin Begin prandial insulin with largest meal Start with 10% of basal dose or 5 units If not at goal can add dose with 2nd and/or 3rd meal Use 15 mins before eating (R is 30 mins) Avoid complicated sliding scales

Basal Bolus With All Meals Begin prandial insulin before each meal 50% basal & 50% prandial(TDD 0.3-0.5 units/kg) Start 50% of TDD in 3 doses before meals

Concentrated InsulinWhen daily insulin requirements are in excess of 200 units/day, the volume of U100 injected insulin may become an issue Physically too large for a single SC administration Multiple injections are required to deliver a single dose Increased injections may lead to compliance issues and poor glycemiccontrol Discomfort Unpredictable absorption (rate-limiting step in insulin activity)

Concentrated Glargine U-300 U-300 insulin glargine offers a smaller depot surface area, leading to areduced rate of absorption Provides flatter and prolonged pharmacokinetic and pharmacodynamicprofiles and more consistency compared to U100 glargine Half-life is 23 hours, blood glucose control beyond 24 hrs Steady state in 4 days Duration of action 36 hours FDA approved February 25, 2015 (Toujeo )

Degludec U-100 & U-200Available only as FlexTouch pens U-200: 600 units/pen, max 160 units/inj U-100: 300 units/pen, max 80 units/inj Duration of action 42 hours Half-life 25 hours Detectable for at least 5 days Steady state in 3-4 days

Humulin R U-500 Insulin Patients on high dose, 200 units daily, 5xs potent Onset 30 mins, duration up to 24 hrs Time action characteristics reflecting prandial & basal activity U-500 Kwick Pen: can deliver 300 units in a single injection, dials in 5 unitincrements, 1500 units in each pen Still comes in vial but requires specific syringe

Walmart Insulin Novolin N: 12 hour acting, twice daily dosing Novolin R: meal time insulin, 30 mins before meal Novolin 70/30 or 75/25; Split mixed, twice daily dosing Vial: 25, Box of pens: 40

Financial Assistance 99 per month programs for insulin Insulin and non insulins at no cost Lilly: lillycares.com (Humalog, Basaglar, U-500) Novo: Novocare.com (Tresiba, Levemir, Novolog, Fiasp) Sanofi: sanofipatientconnection.com (Lantus, Toujeo, Admelog,Apidra)

What’s Next?

Clinical Trials Clinicaltrials.gov Medications in phase 3 trials Local pharmaceutical reps can not discuss medications that are intrial Can only discuss FDA approved medications

Tirzepatide GLP1/GIP dual therapy (new class/category) Both GIP and GLP-1 are hormones secreted by the gut in responseto nutrients. They are responsible for the incretin effect, whichenhances the secretion of insulin after a meal GIP also impacts weight related mechanisms Once weekly injectable Dosing: 5 mg, 10 mg, 15 mg Promising data in regards to A1c and weight reduction

Insulin Icodec Once weekly long acting insulin Terminal half life of 196 hours Primary end point: Percent of time in range monitored with CGM Secondary endpoint: A1c reduction, hypoglycemia, and adverseevents

Continuous Glucose Monitoring Dexcom, Libre & Libre 2 No finger sticks, data sharing with HCPs remotely Monitor BS as frequently as desired Audible alarms (Dexcom, Libre 2) Trending arrows showing direction of BS Can use receiver or smart phone if compatible Share data with family

Libre Freestyle Continuous GlucoseSensor-Intermittent Scan

Dexcom G6 Continuous GlucoseSensor-Real Time (iCGM)

CGM Insurance Requirements Type 1 DM or Type 2 DM on intensive insulin therapy (MDI/pump) Testing BS 4 times daily (Medicare dropped this 7/18/2021) Meal time insulin and self adjusting doses or sliding scale This must all be in you visit note and the ICD-10 Will include inhaled insulin (Afrezza) Community Walgreens

Dexcom Prescribing Receiver: 1 unit every 5 years Transmitter: 1 unit every 3 months Sensors: 3 sensors per month

Libre, Libre 2 Receiver-1 every 5 years Sensors-2 per month

Near Future of CGM

Companion Medical InPen Reusable pen for short acting, meal time insulin Humalog or Novolog cartridge Bolus calculator Real time insulin-on-board tracking Reminders to avoid missed meal doses Insulin temp monitor InPen app receives CGM data (24 hr avg/summary trends) Auto texts with each interaction (up to 5 recipients)

InPen Insights Report

InPen Requirements Must be able to count carbohydrates Must be monitoring blood glucose at least 3 times daily If able to master InPen it is a smother transition to a pump Meet with CDE to calculate I:C ratio & ISF/Correction Must down load application Share Insights Report via MyChart

Summary Consider medications that offer CV risk reduction and weightreduction Consider medications that slow progression of CKD Do not hesitate to start long acting insulin 10 units daily Consider CGM in patients who qualify

Tirzepatide GLP1/GIP dual therapy (new class/category) Both GIP and GLP-1 are hormones secreted by the gut in response to nutrients. They are responsible for the incretin effect, which enhances the secretion of insulin after a meal GIP also impacts weight related mechanisms Once weekly injectable Dosing: 5 mg, 10 mg, 15 mg Promising data in regards to A1c and weight reduction