Type 2 Diabetes: Update on Newer Medications for Inpatient Physicians Timothy W. Bodnar, MD September 7, 2017

Disclosures I have no conflicts to disclose

A note on medication names As many patients will only know their medications by trade name, I will be using both generic and trade names to ensure more accurate communication at transitions of care: Generic (Trade)

Educational Objectives Review inpatient glycemic management guidelines/goals Identify newer oral and injectable medications for diabetes to: Improve hospital physician familiarity and Ensure more accurate communication at transitions of care Translate home diabetes medications to insulin-based hospital regimens

Lansang MC and Umpierrez GE. Cleve Clin J Med, 2016

American Diabetes Association. Diabetes Care, 2017 ADA Standards of Medical Care in Diabetes: Diabetes Care in the Hospital Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold 180 mg/dL. Once insulin therapy is started, a target glucose range of 140–180 mg/dL is recommended for the majority of critically ill patients and non-critically ill patients. An insulin regimen with basal, nutritional, and correction components is the preferred treatment for noncritically ill hospitalized patients with good nutritional intake. Sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged. American Diabetes Association. Diabetes Care, 2017

“Doc, I’m not sure about the names of my medications “Doc, I’m not sure about the names of my medications. They’re in the computer. I know I take 2 shots…”

GLP-1 receptor agonists Exenatide (Byetta – BID, Bydureon – QW) Liraglutide (Victoza – QD) Liraglutide with degludec (Xultophy – QD) Albiglutide (Tanzeium – QD) Dulaglutide (Trulicity – QW) Lixisenatide (Adlyxin – QD) Lixisenatide with glargine (Soliqua – QD)

GLP-1RAs: CV, renal benefit? LEADER: liraglutide (Victoza) “In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.” “…when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo.” Marso SP, et al. N Engl J Med, 2016 / Mann JFE, et al. N Engl J Med, 2017

Marso SP, et al. N Engl J Med, 2016

Mann JFE, et al. N Engl J Med, 2017

GLP-1RAs: Safety? Pancreatitis, pancreatic cancer risk? “Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported zero events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms (MH-OR [95% CI] 0.93 [0.65-1.34], p = 0.71, and 0.94 [0.52-1.70], p = 0.84, respectively.), whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], p = 0.041) was detected.” Monami M, et al. Diab Obes Metab, 2017

GLP-1RAs: Transitions of Care STOP USING UPON ADMISSION Replace with prandial/mealtime insulin Resume when patient returns home if: Taking regular oral nutrition No pancreatitis No unresolved nausea/vomiting/diarrhea

SGLT-2 inhibitors Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance)

SGLT-2Is: CV, renal benefit? EMPA-REG: empagliflozin (Jardiance) “Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause…” In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo…” Zinman B, et al. N Engl J Med, 2015 / Wanner C, et al. N Engl J Med, 2016

Zinman B, et al. N Engl J Med, 2015

Zinman B, et al. N Engl J Med, 2015

Wanner C, et al. N Engl J Med, 2016

SGLT-2Is: CV, renal benefit? CANVAS: canagliflozin (Invokana) “Patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo…” CVD-REALNordic: 94% dapagliflozin (Farxiga) “In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs” Neal B, et al. N Engl J Med, 2017 / Birkeland KI, et al. Lancet Diabetes Endocrinol, 2017

Neal B, et al. N Engl J Med, 2017

SGLT-2Is– Safety? Hyperkalemia DKA (usually with other trigger) Stop 3 days before OR Yeast infections > UTIs Foot amputations – canagliflozin (Invokana)

SGLT-2Is: Transitions of Care STOP USING UPON ADMISSION Be vigilant for signs/symptoms of DKA even if glucoses not terribly high Both fasting and postprandial glucoses will rise when discontinued Resume when you would resume metformin Hold canagliflozin (Invokana) if any concern for PAD, diabetic foot infection

Concentrated insulin Human insulin (Humulin-R U-500 concentrated insulin): 500 units per mL (compared to 100 units per mL) “Regular” insulin (Humulin-R U-100) – 50 units U-500 concentrated insulin (Humulin-R U-500) – 50 units

U-500 concentrated insulin: Transitions of Care PER HOSPITAL POLICY, WE DO NOT USE Transition to U-100 basal-bolus insulin: Find out how many units patient takes in total per day Typically will need ~50-70% of that for total daily dose in hospital Divide 50-50 between basal and bolus Example: “I take 24 units 3 times a day” Using usual insulin syringes, actually takes 120 units x 3 = 360 units 360/2 = 180 units Insulin glargine 90 units/day, insulin lispro 30 units TID-meals Caveat: concentrated regular human insulin (Humulin-R U-500) now comes in a pen that delivers the exact units…

Newer insulin options Lispro (Humalog) now with a U-200 pen 600 units/pen, 2 pens/box Glargine (Toujeo) now with a U-300 pen 450 units/pen, 3 pens/box Glargine (Basaglar) now 1st “biosimilar”, in pen Degludec (Tresiba) now with U-100 or U-200 pen U-100: 300 units/pen, 5 pens/box U-200: 600 units/pen, 2 pens/box Much longer, flatter profile than Lantus – daily dosing at any time of day Good for forgetful patients or those with nocturnal hypoglycemia

Newer basal insulins: Transitions of Care Glargine biosimilar (Basaglar) Glargine concentrated (Toujeo U-300) Degludec (Tresiba, whether U-100 or U-200) The above concentrated insulins ONLY come in pens so you don’t have to worry about volume conversions Do exactly what you would do if patient takes insulin glargine (Lantus) at home

Lispro (Humalog U-200): Transitions of Care Do exactly what you would do if patient takes lispro (Humalog) or aspart (Novolog) at home

Insulin “Patch”: V-Go V-Go “insulin delivery device” https://www.go-vgo.com/

V-Go: Transitions of Care Can pull off like a bandaid – be ready for a few drops of blood Immediately remove if: Hypoglycemic AMS Critically ill Imaging study To convert to injections, determine if V-Go 20, 30, or 40, and ask patient how many clicks per meal (1 click = 2 units)

V-Go: Transitions of Care 20 units across 24 hours (“basal”) Up to 36 units in 2-unit increments (“bolus”) V-Go 30: 30 units across 24 hours (“basal”) V-Go 40: 40 units across 24 hours (“basal”)

V-Go: Transitions of Care Example: V-Go 30 = 30 units of insulin across 24 hours  glargine (Lantus) 30 units every 24 hours, 1st dose when V-Go removed 6 clicks per meal = 12 units per meal  lispro (Humalog) 8 units per meal Can do 1:1 translation, but as patients generally eat less while in-house, I’d suggest lowering by 25-33%

Lansang MC and Umpierrez GE. Cleve Clin J Med, 2016

Lansang MC and Umpierrez GE. Cleve Clin J Med, 2016

References American Diabetes Association. Standards of medical care in diabetes 2017. Diabetes Care, 2017;40(Suppl 1):S1–S135. Birkeland KI, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REALNordic): a multinational observational analysis. Lancet Diabetes Endocrinol, 2017;5:709-17. Lansang MC and Umpierrez GE. Inpatient hyperglycemia management: a practical review for primary medical and surgical teams. Cleve Clin J Med, 2016;83(5 Suppl 1):S34-43. Mann JFE, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med, 2017;377:839-48. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2016;375:311-22. Monami M, et al. Safety issues with Glucagon-Like peptide-1 receptor agonists: Pancreatitis, pancreatic cancer, and cholelithiasis. data from randomised controlled trials. Diabetes Obes Metab, 2017;epub ahead of print Mora PF and Johnson EL. Cardiovascular outcomes trials of the incretin-based therapies. What do we know so far? Endocr Pract, 2017;23:89-99. Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med, 2017;377:644-57. Wanner C, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med, 2016;375:323-34. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med, 2015;373: 2117-28. https://www.go-vgo.com/