What’s New in Type 2 Diabetes? 2018 Diabetes Updates Gretchen Ray, PharmD, PhC, BCACP, CDE Associate Professor, UNM College of Pharmacy January 28, 2018 gray@salud.unm.edu

Objectives Describe the most recent drug approvals for type 2 diabetes and the cardiovascular outcome data supporting the newer drug classes Describe the 2018 Treatment recommendations from the American Diabetes Association Given a patient case, utilize a patient centered approach when selecting pharmacotherapy options for a patient with type 2 diabetes

Updated guidelines Standards of Medical Care in Diabetes 2018. Diabetes Care 2018;41(Suppl 1)

Diabetes Medications 1960 1995 2000 2005 2010 2015 2016 2017 Insulin Canagliflozin Alogliptin 2013 Dapagliflozin Empagliflozin Albiglutide Dulaglutide Afrezza inhaled insulin 2014 Diabetes Medications Saxagliptin 2009 U-300 Glargine Insulin Degludec Basaglar 2015 Semaglutide Ertugliflozin Fiasp Admelog 2017 Sitagliptin 2006 Insulin 1922 SUs 1957 Metformin AGIs 1995 Linagliptin 2011 1960 1995 2000 2005 2010 2015 2016 2017 Glinides TZDs 1997 Exenatide Pramlintide 2005 Liraglutide 2010 Plethora of new drugs over last 5 years Exenatide/Byetta-first GLP-1 & incretin Pramlinitide/Symlin: amylin mimetic, injectable for T1DM and T2DM; will not discuss today Sitaglilptin/Januvia/Janumet: October 2006, first DPP-4 inhbitor, oral agent Saxagliptin/Onglyza: July 2009, second DPP-4 inhbitor, oral agent Liraglutide/Victoza: January 2010, second GLP-1 agonist, injectable once daily formulation 2012 Exenatide LAR 2016 Glargine/lixisenatide Degludec/liraglutide

Types of Insulin Rapid Acting Short Acting-Regular Insulin (R) Humalog®, Admelog® (lispro) (U-100 and U-200-Humalog® only) Novolog ®, Fiasp® (aspart) Apidra ® (glulisine) Short Acting-Regular Insulin (R) Novolin® R Humulin® R Intermediate Acting-NPH (N) Novolin® N Humulin ® N Long Acting – Basal Insulin Levemir® (detemir) Lantus®/Basaglar ® (U-100 glargine) Toujeo® (U-300 glargine) Tresiba®(Degludec U-100 and U-200)

Insulin Lispro (admelog®): Approved December 2017 First follow-on insulin lispro Similar to insulin lispro (Humalog®) Available in U-100 vials and the Solostar® Pen No dose conversions when switching from other rapid acting insulins

Faster acting insulin aspart (fiasp®): Approved 9/2017 Insulin aspart + added niacinamide to speed absorption + L-arginine as a stabilizing agent Faster aspart vs. insulin aspart in type 1 patients pooled analysis1 5 min earlier onset of insulin exposure 2 x higher early insulin exposure Offset of exposure and glucose lowering effect 12-14 min earlier with faster aspart Inject at start of meal or up to 20 minutes after the start of a meal Novolog® approved to inject 5-10 minutes before the meal 1. Heise et al. Clin Pharmacokinet 2017;56:551-59

Counseling considerations New concentrations of Glargine U-300, Degludec U-200, and now Insulin Lispro (Humalog®) U-200 Caution patients not to use syringes to draw insulin out of their pens Different storage criteria of in use pen for each product New brand names as follow-on insulins Frequent formulary changes

GLP-1 Receptor Agonists

GLP-1 Physiology

GLP-1 agents Exenatide (Byetta®) BID dosing timed with meals Liraglutide (Victoza®) Once daily dosing Dulaglutide (Trulicity®) Once weekly dosing Lixisenatide (Adlyxin®)- once daily. FDA approved not not yet available in US as monotherapy Albiglutide (Tanzeum®)- Will be removed from the market in 2018

Exenatide Long Acting: update 2 mg subq once a week Without regard to meals or time of day New Bydureon® BCise™ Pen approved- Available in 2018 Single use autoinjector device Original pen

Semaglutide (Ozempic®): Approved December 2017 Titration dose: 0.25 mg once a week Increase to 0.5 mg after 4 weeks. Max dose 1 mg 0.25/0.5 mg: 1 pen + 6 needles/box 1 mg pen: 2 pens + 4 needles/box Priming step with each new pen

GLP-1 agonist adverse effects/Precautions Nausea and vomiting –most common AE Cases of acute pancreatitis Contraindications/Precautions eGFR <30, do not use exenatide Gastroparesis History of pancreatitis History of medullary thyroid carcinoma Multiple endocrine neoplasia syndrome 2 At low titers, the antibodies do not affect the effectiveness of exenatide. Delays gastric emptying. Counsel patients to take their other meds 1 h before byetta

GLP-1 Agonist Benefits Low risk of hypoglycemia Weight loss Slightly higher risk when used with sulfonylureas or insulin Weight loss Potential for once daily or once weekly dosing Studies have shown addition to a basal insulin can be as effective as starting a pre- meal insulin – see ADA insulin dosing algorithm Standards of Medical Care in Diabetes 2018. Diabetes Care 2018;41(Suppl 1)

GLP-1 Agonist/Basal Insulin Combination Pens

Insulin glargine & Lixisenatide (Soliqua™ 100/33 Solostar® Pens) Combination of insulin glargine 100 units/mL and lixisenatide 33 mcg/mL Available in pen form 1 box = 5 pens = 1500 units Approved for patients uncontrolled on a basal insulin Once daily dosing Dosing: Patients on <30 units basal insulin: start 15 units of Soliqua™ 100/33 Patients on >30 units basal insulin: start 30 units of Soliqua™ 100/33 Titration is similar to basal insulin alone…increase by 2-4 units/week until fasting glucose <130 mg/dL Max dose is 60 units If patient requires >60 units of basal insulin, use a different/individual drugs

Insulin Degludec and Liraglutide (Xultophy™ 100/3.6) 100 units Insulin degludec + 3.6 mg liraglutide/mL Dose range 16-50 units once a day Start patients on 16 units once a day Titrate by 2 units every 3-4 days until fasting glucose at goal Max dose 50 units (=50 units degludec + 1.8 mg liraglutide) 1 box = 5 pens = 1500 units

GLP-1 RA CV Safety Trials

Leader: liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results Evaluated liraglutide vs. placebo + standard of care in patients with type 2 diabetes and high risk of CV disease or with established CV disease Median follow-up 3.8 years Primary outcome: first occurrence of death from CV cause, non-fatal MI or non-fatal stroke Primary outcome occurred in 13.0% liraglutide vs. 14.9% in placebo group (p<0.001 for non-inferiority; p=0.01 for superiority) FDA indication to reduce risk of CV death, nonfatal MI or nonfatal stroke 13% relative risk reduction N Engl J Med 2016;375:311-22

Secondary Analysis of Renal Outcomes Leader: liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results Secondary Analysis of Renal Outcomes Composite of new onset persistent macroalbuminurea, persistent doubling of serum creatinine level, end-state renal disease, or death due to renal disease Renal outcome occurred in fewer patients in liraglutide group (268/4668 vs. 337/4672 HR, 0.78; p=0.003) NEJM 2017;377(9):839-48

SUSTAIN-6: Semaglutide CV Safety Trial Trial design: Patients with DM2 at high risk for CV events were randomized in a 1:1:1:1 fashion to either semaglutide 0.5 mg, semaglutide 1 mg, or matching placebo. They were followed for a median of 2.1 years. Results pnoninferiority < 0.001 psuperiority = 0.02 Primary outcome, CV death/MI/stroke: semaglutide vs. placebo: 6.6% vs. 8.9%, HR 0.74, 95% CI 0.58- 0.95, p < 0.001 for noninferiority; p = 0.02 for superiority CV death: 2.7% vs. 2.8%, p = 0.92; all MI: 2.9% vs. 3.9%, p = 0.12; all stroke: 1.6% vs. 2.7%, p = 0.04 HbA1c at week 104: 7.6% vs. 7.3% vs. 8.3% % Conclusions Injectable once a week semaglutide (GLP-1 agonist) was superior to placebo in improving glycemic control and ↓ CV events in high-risk patients with diabetes Primary outcome Semaglutide (n = 1,648) Placebo (n = 1,649) Marso SP, et al. N Engl J Med 2016;375:1834-44

GLP-1 RA CV Studies demonstrating non-inferiority ELIXA1-lixisenatide EXSCEL2- exenatide LAR Pfeffer MA, et al. NEJM. 2015;373(23):2247-57 Holman RR, et al. NEJM. 2017 Sept 14; epub ahead of print

SGLT2 Inhibitors

Sodium- glucose co- transporter inhibitors (SGLT2) SGLT2 INHIBITORS Sodium- glucose co- transporter inhibitors (SGLT2) Increase urinary glucose excretion Sodium glucose co-transporter 2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen.. Inhibiting SGLT2, it reduces reabsorption of filtered glucose and lowers the renal threshold for glucose increasing urinary glucose excretion.

SGLT2 InhibitorS Canagliflozin (Invokana™) Dapagliflozin (Farxiga™) Empagliflozin (Jardiance™) Ertugliflozin (Steglatro™)- Newly approved 12-2017 Once daily oral medications Low risk of hypoglycemia Weight loss 20 hospitalizations between March 2013 and June 2014 reported in the FDA AERS Large phase 3 trials have shown no signs of DKA.

SGLT2 Inhibitors Side Effects/Precautions Benefits Female genital mycotic infections UTI Increased urination Hypotension due to volume depletion Hyperkalemia Euglycemic ketoacidosis Rare but recent FDA warning Possible fracture risk? Amputation risk with canagliflozin? Benefits Once daily oral agents Insulin independent action Small weight loss in studies Low risk of hypoglycemia

SGLT2 Inhibitor CV Safety Trials

EMPA-REG OUTCOME study 7020 patients with established CVD randomized to empagliflozin or placebo Primary composite outcome: death from CV cause, nonfatal MI, or nonfatal stroke 10.5% in empagliflozin group vs. 12.1% placebo p=0.04 for superiority Death from CV causes: 3.7% empagliflozin 5.9% in placebo 38% relative risk reduction Zinman B, et al. NEJM 2015. 373 (22):2117-28

Empa-reg:CV death, MI and stroke Patients with event/analyzed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Table 15.2.4.1.1: 1 Table 15.2.4.1.2: 1 Table 15.2.4.1.3: 1 Table 15.2.4.1.5: 1 Table 15.2.4.1.8: 1 Table 15.2.4.1.9: 1 Favors empagliflozin Favors placebo Zinman B, et al. NEJM 2015. 373 (22):2117-28

Canvas and canvas-R Canagliflozin CV safety and renal outcome study Included patients >30 years with established ASCVD or >50 years with 2 or more risk factors Primary outcome: composite of death from CV cause, non-fatal MI or non-fatal stroke Neil B, et al. NEJM 2017;377(7):644-657

Canvas and canvas-R Neil B, et al. NEJM 2017;377(7):644-657

Canvas and canvas-R Renal outcomes Neil B, et al. NEJM 2017;377(7):644-657

Canvas and canvas-R Safety endpoints Newly identified amputation risk in the canagliflozin group 6.3 vs. 3.4 events/1000 pt years (HR 1.97 [CI 1.41-2.75]) Mechanism unknown Possible increased risk of fracture Other side effects were similar to other SGLT2 inhibitor trials Neil B, et al. NEJM 2017;377(7):644-657

SGLT2-I CV Safety trials in progress Dapagliflozin: DECLARE-TIMI58 Estimated completion July 2018 Ertuglifozin: Vertis CV Study Estimated completion October 2019

ADA Management of Hyperglycemia in Type 2 Diabetes Standards of Medical Care in Diabetes. Diabetes Care 2018;41(Suppl 1)

Antihyperglycemic Therapy in Adults with T2DM The first step in the management of newly diagnosed type 2 diabetes is highlighted at the top of the algorithm: initiate lifestyle management, set A1C target, and initiate pharmacotherapy based on A1C at diagnosis. For those with an initial A1C less than 9%, monotherapy may be considered, while those with an A1C greater than 9% should consider dual therapy, and those with A1C greater than 10%, high blood glucose (>300 mg/dl), or symptoms of hyperglycemia may consider combination injectable therapy, which I’ll detail shortly. The initial preferred agent remain metformin, though other therapies may be considered if metformin is contraindicated or isn’t tolerated. If A1C target is not achieved or maintained within 3 months, or at any point, lifestyle management should be reinforced and dual therapy considered. [SLIDE] Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 37

Antihyperglycemic Therapy in Adults with T2DM Liraglutide or Empagliflozin Can consider canagliflozin Starting with dual therapy, the algorithm has been updated this year to incorporate consideration of ASCVD at the point of dual therapy given results of recently published cardiovascular outcome trials. As noted in the algorithm, in patients who do not have atherosclerotic cardiovascular disease (ASCVD), consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin; the choice of which agent to add is based on drug specific effects and patient factors, as highlighted in Table 8.1 which will be highlighted in the next slide. For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors. If A1C target is still not achieved after 3 months of dual therapy, proceed to a three-drug combination. Again, if A1C target is not achieved after ~3 months of triple therapy, proceed to combination injectable therapy. At each step, lifestyle management should be reinforced and medication-taking behavior assessed. [SLIDE] Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 38

Drug factors to consider

Drug factors to consider Class Efficacy Hypo Wt Change CV Events Cost Oral/ SQ Renal Effects Other considerations ASCVD CHF DKD Dosing/ use SGLT-2 Inh. Intermed no loss Benefit: cana empa high oral GFR adjustments Cana risk of amputation & bone fx GU infection Volume depletion hypotension GLP-1 RA High Liraglutide benefit neutral Benefit: liraglutide Exenatide CI if GFR<30 FDA Box warning: thyroid C-cell tumors GI side effects Injection site reaction Pancreatitis? Standards of Medical Care in Diabetes. Diabetes Care 2018;41(Suppl 1)

Approach to starting and adjusting insulin in type 2 diabetes Approach to starting and adjusting insulin in type 2 diabetes. FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo, hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. Diabetes Care, 2015;38:140-149 References American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37(suppl 1):S27–S28 Blonde L,MerilainenM, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets the TITRATE study. Diabetes Obes Metab 2009;11:623–631 Inzucchi SE, Bergenstal RM, Buse JB, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379 41

Considerations when adding on therapy to metformin Choice is based on patient and drug characteristics Use ADA algorithm and knowledge of pharmacology, cost, patient preference, and side effect profile Consider insulin +/- other agents in newly diagnosed patients with glucose >300 and/or A1C >10% or symptomatic Consider initiating dual therapy in newly diagnosed patients with A1C >9% In patients with diabetes and established ASCVD, empagliflozin or liraglutide should be incorporated as they have been shown to reduce CV and all-cause mortality Canagliflozin can also be considered Standards of Medical Care in Diabetes. Diabetes Care 2018;41(Suppl 1)

Questions