What hospitalists need to know about diabetes…

Elizabeth Stephens, MD, FACP PMG- Endocrinology [email protected] September 2019 Disclosures •OHSUNone Objectives

• Review medications used commonly for type 2 diabetes • Discuss strategies for insulin management • Describe technologies being used for type 1 and 2 diabetes (pumps and sensors) •OHSUOutline issues specific to admission for medications and technologies Case #1

• 62 yo woman, type 2 DM x 9 years, history of MI, dx with CHF last month- controlled • Currently on metformin 500mg QD, glipizide 10mg bid, pioglitazone 45mg QD •OHSUA1c 9.2%, BMI 42 • Normal renal & liver function • Complains of fatigue Considerations:

• Would you continue her on her current regimen?

• What would you consider adding?

•OHSUWhat would you target for A1c? TYPE 2 DIABETES 12 Different Classes of Therapy

Reduce Hepatic Glucose Insulin Sensitizers Production – Thiazolidinediones –Metformin + XR • Pioglitazone (Actos) Enhance Insulin Secretion/Effect SGLT 2 Inhibitors –Sulfonylureas • Canagliflozin (Invokana), Dapagliflozin (Farxiga), • Glipizide, glyburide, glimepiride Empagliflozin (Jardiance) –Meglitinides (short acting) Incretin Therapies • Repaglinide (Prandin), nateglinide (Starlix) – GLP Analogs –Insulin- injectable • Exenatide (Byetta), XR weekly • Liraglutide (Victoza), Attenuate Glucose Absorption semaglutide(Ozempic), dulaglutide –-glucosidase inhibitors (Trulicity), lixisenatide (Adlyxin) OHSU• Acarbose (Precose) • Miglitol (Glyset) - DPPIV Inhibitors Other: • Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta), - Bromocriptine Alogliptin (Nesina) - Salsalate - Colesevelam - Amylin Analogs (Symlin) Sulfonylureas • Considerations: – A1c lowering 1-1.25%, inexpensive – Glyburide WORST for hypoglycemia • 2-fold ↑ risk c/w glipizide in elders, and 52% ↑ risk of hypoglycemia c/w other SU’s (J Manag Care Pharm 2011;17:664) • Glipizide and glimepiride better alternatives OHSU– All associated with weight gain – Glinides (repaglinide or nateglinide) dosed before meals another consideration Metformin • Considerations: – Lowers A1c 1-1.5% – Weight neutral, less hypoglycemia risk, ↓ CVD (UKPDS), no age cut-off – XR tends to be easier to tolerate (GI) – Check eGFR OHSU• Contraindicated if <30mL/min/1.73m2 • Don’t start if between 30-45mL/min/1.73m2 • If eGFR < 45mL/min/1.73m2, consider ↓ dose – Follow renal function annually, or more often if at risk, and use care with CHF or liver disease Pioglitazone • Considerations: – A1c lowering:1-1.5%, lower cost – Less hypoglycemia, durable effect but takes > one month to get to steady state – Issues with fluid retention, weight gain • Generally seen with higher doses and worse when OHSUused with insulin – Bone loss and increased fracture rates in women – Prevents fibrosis in those with NASH, reduces inflammation in those with fatty liver Bril F et al, Diabetes Care

2017;40:419 DPP- 4’s Examples: Alogliptin, saxagliptin, linagliptin,sitagliptin • Considerations: – A1c lowering: < 1%, $250-500/month – Low risk of hypoglycemia and weight neutral; oral – Concerns with fluid retention/CHF with OHSUsaxagliptin and alogliptin – No renal adjustment for linagliptin – Pancreatitis reported but rare GLP-1 Receptor Antagonist Examples: Exenatide XR, Dulaglutide, Semaglutide, • Considerations: Liraglutide – A1c lowering: 1-1.5%, $630-870/month – Weekly is useful for reluctant injectors – Weight loss • Semaglutide (Ozempic®) > liraglutide (Victoza®) > dulaglutide(Trulicity®) > exenatide XR (Bydureon®) > lixisenatide (Adlyxin®) – CV benefit: Liraglutide (Victoza®) > semaglutide OHSU(Ozempic®)> exenatide XR (Bydureon®) – Avoid in those with history of pancreatitis (Etoh and TG’s) and medullary thyroid cancer (rare) – Remember ALL GLP-1’s provide more weight loss c/w insulin Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2I) OHSU SGLT2-Inhibitors Examples: Dapagliflozin, canagliflozin, empagliflozin • Considerations: – A1c lowering: .5-1%, $400-500/month – Oral, less hypoglycemia risk – Pros: • Weight loss (1-3kg), BP ↓ (3-4mmHg) • CV benefit- empagliflozin (Jardiance®) + canagliflozin

(Invokana®)-Canvas, NEJM 2017; EMPA-REG, NEJM 2015 • Reduction in proteinuria, GFR benefit OHSU– Cons: • Genital infections, DKA, bone loss/fracture risk, volume loss, Fournier’s gangrene • Amputation risk with canagliflozin Euglycemic DKA with SGLT-2i’s • Cause • Treatment – ↑ glucagon release, – Hold/stop SGLT2i dehydration, ↓ ketone – Ingest 15-30 grams of clearance rapid CHO • Risk factors – Fluids hourly, 300-500ml – Reduction in insulin, – Administer insulin hourly low carb diet, – Check urine/blood OHSUetoh/drug use, volume ketones every 3-4 hours depletion, acute until resolved illness/vomiting

Peters AL, Diabetes Care 2019;42(6):1147 Third-Agent Considerations Medication Pros Cons DPP-4 - Less hypoglycemia - Cost $$ - Good for elderly, renal - Potency impairment (linagliptin) - Pancreatitis, CHF - Few side effects (pancreatitis) TZD - Beneficial with fatty liver, stroke - Edema, weight gain, fx - Lesshypoglycemia - Durability - Cost

SGLT-2 - ↓ wt, BP - Cost $$ - Rare hypoglycemia - GU infections, Fournier’s - ↓ CV events/mortality - Polyuria/vol loss, bones OHSU- Renal protection - DKA

GLP-1 RA - Wt loss - Cost $$ - Less hypoglycemia - Injectable - CV benefit - Pancreatitis - GI side effects Case #1: • Would you continue her on her current regimen? ↑Metformin(change to XR) + glipizide, follow renal function, consider d/c of SU if hypoglycemia an issue • Anything you would change? Stop Pioglitazone with CHF • OHSUWhat would you consider adding? Empagliflozin or GLP-1 (Semaglutide, Liraglutide) • Target for A1c? <7-7.5% Case # 2 • 53 year-old woman with type 2 diabetes for 12 years, BMI 42, limited income • Currently on metformin, glimepiride – Tried on other medications but couldn’t afford • Limited monitoring, but most readings > OHSU200mg/dl, A1c 10.3% • Also symptomatic with polyuria, significant fatigue, recurrent yeast infections Key • Analog: Modified • Longer-acting : human insulin to act – NPH: Novolin®, faster or slower Humulin®, Relion® • Short-acting: – Glargine: Lantus® • Basaglar – Lispro: Admelog®, • U300: Toujeo® Humalog® – Detemir: Levemir® – Aspart: Novolog® OHSU– Degludec: Tresiba® – Glulisine: Apidra® • U100 and U200 – Regular - Novolin ®, Humulin ®, Relion® – Afrezza® Options for insulin Basal- Insulin Onset Peak Duration Cost NPH 1-2 hrs 4-8 hrs 14-18 hrs $25-300 Detemir 1-2 hrs 4-6 hrs 12-20 hrs $300-450 Glargine 1-2 hrs Flat/3 hrs 22-24 hrs/24- $190-250 36 hrs (U300) Degludec 1-2 hrs 9-10 hrs 42 hours $450-550

BolusOHSU- Insulin Onset Peak Duration Cost Regular 30-60 min 2-4 hrs 4-8 hrs $25-140

Aspart, lispro, 5-15 min 1-2 hrs 3-5 hrs $180-500 glulisine Insulin updates: • Afrezza® (inhaled insulin) • Ademlog® (insulin lispro): biosimilar, no difference in efficacy/safety, cannot be substituted in pharmacies • Fiasp®(insulin aspart): new ultra-rapid insulin, peak 1.5-2.2 hrs, approved to be dosedOHSU up to 20 min after eating • Basaglar® (insulin glargine): biosimilar, no difference in outcomes, only in pens, no substitutions My opinion on New Basal Insulins

Pros/considerations Cons

Degludec - Shift workers - Only available in (Tresiba®, - Missed doses pens U100 and - BID long-acting - Cost - Variable BG U200) - Big doses (up to 160u) U300OHSU - Missed doses - May require ↑ dose Glargine - BID long-acting amount (up to 20%) (Toujeo®) - Variable BG - Cost Adding Basal Insulin ADA Algorithm- 2019 • Indicated with A1c> 9%, symptoms, ? Type 1 • Start 10U/day, or .1-.2units/kg/day – Bedtime or AM, depending on pattern/adherence • Adjust 10-15% or 2-4U once/twice weekly to reach FPG target OHSU– Generally fasting goals of 80-130mg/dl • Maybe higher in certain populations • For hypoglycemia: determine cause – ↓ dose by 4U or 10-20% Comparing Insulins

• In terms of A1c: – Degludec = glargine = detemir = NPH • Small differences in weight – Less with detemir and Glargine-U300 • Less nocturnal hypoglycemia OHSU– Degludec, Glargine-U300 – No difference in severe hypoglycemia Starting insulin • Rotating injection sites, using fresh needles, needle length (4mm vs 8mm) • Needle disposal • Hypoglycemia education- rule of 10-15 • Monitoring frequency and glucose OHSUtargets • Be careful with sliding scales • Diabetes education What about other agents when adding insulin? • GLP1, DPP-4 SGLT-2, Metformin: • May reduce wt gain/dose needed • May worsen hypoglycemia risk • Sulfonylurea (SU): • Better post-prandial BG, but ↑ hypoglycemia OHSU• Consider d/c when meal insulin started • TZDs: • Increased risk for edema with insulin

Wallia A, Molitch M. JAMA 2014;311:2315; Diab Care Supp 2019 Case # 2 • 53 year-old woman with type 2 diabetes 12 years, BMI 42, limited income • Currently on metformin, glimepiride • Limited monitoring, but most readings > 200mg/dl, A1c 10.3% • Also symptomatic with polyuria, significant OHSUfatigue, recurrent yeast infections • Would start on 15-20units of NPH in the evening, and ask for morning BG Inpatient issues with insulin

• Ultra-long acting insulins – Long-acting degludec, convert 1:1 to glargine – Takes 3-4 days to get to steady state- warn OHSUpatients with discharge • Education-monitoring, hypoglycemia • Cost – Many formulary issues with insulins Case #3

• 37 yo with type 1 dm – > 18 years, varied symptoms with hypoglycemia • Monitoring BG 3-5x per day •OHSUFrustrated by variability in BG readings • Wondering about new tools that might be helpful? Continuous glucose monitoring • Reads glucose levels in subcutaneous tissue, calibrates to blood • Benefits include lack of fingersticks, feedback, reduced risk of hypoglycemia • 3 currently available: – Freestyle Libre®, Dexcom G6® and Medtronic OHSUGuardian® CGM options OHSU Utility of sensors • Information about slope/change vs snapshot • Notification of patterns, alarms • Very useful for engaged patients, limited monitoring •OHSUSmall studies with inpatients, inconclusive – Varied devices, outcomes – Telemetry- model being explored Comparison of Data OHSUOR What are pumps? • Continuous infusion of insulin into SQ tissue – Only mealtime (lispro or aspart), no long-acting • Programmed to deliver basal rate hourly • Boluses determined by wearer based on carbs with meal, glucose level – Use calculators that give dose recommendations • ManyOHSU now integrated with sensors, and adjusting insulin based (artificial pancreas) • 3 currently available: Medtronic®, Omnipod® and Tandem/Tslim® Pump and Sensor Examples OHSU Contraindications to insulin pump use in the hospital: • Impaired level of consciousness (except short-term anesthesia) • Inability to demonstrate pump settings • Critical illness/ICU • Psychiatric illness that interferes with ability to manage diabetes or suicide risk • Diabetes ketoacidosis of hyperosmolar OHSUhyperglycemic state • Refusal to participate in self-care • Lack of pump supplies • Lack of trained personnel

Umpierrrez GE, Diabetes Care 2018;41:1579 What to consider with discharge • Long acting insulin – Using temporary basal or waiting a day to put pump back on • If replacing in the hospital, needs to bring supplies, not stocked • EducateOHSU about hypoglycemia • Follow up with endocrine team Objectives

• Review medications used commonly for type 2 diabetes management • Discuss strategies for insulin management • Describe technologies being used for type 1 and 2 diabetes (pumps and sensors) •OHSUOutline issues specific to admission for medications and technologies THE END Questions??OHSU