Diabetes Update 2016: New Drugs and New Methods of Care Kelly Murray, PharmD, BCACP Clinical Assistant Professor of Clinical Pharmacy OSU College of Osteopathic Medicine Emergency Department Clinical Pharmacist OSU Medical Center

2016 FIESTA ACCRA , GHANA HILLCREST HOSPITAL, TULSA, OKLAHOMA USA MICHAEL OPONG-KUSI, MBA, DO,FAAFP HILLCREST HOSPITAL, TULSA, OKLAHOMA USA

DIABETES IN GHANA 2016 FIESTA Growing Obesity and sedentary life style especially in the cities. Carbohydrate rich diet Aging of the population in Ghana Lack of primary medical care and screening

Overview Standards of Care 2016 Updates New Diabetes Therapies 2016 FIESTA Standards of Care 2016 Updates New Diabetes Therapies Oral medications Injectable medications Insulin therapies Innovative Care Solutions and Ideas

Objectives 2016 FIESTA Describe the mechanisms of action of the newest type 2 diabetes medications – DPP4-inhibitors, incretin mimetics, and SGLT-2 inhibitors. Recall advantages of insulin degludec over insulin glargine. Discuss availability and price of these new drugs in Ghana.

Standards of Care 2016 Updates Mm

General Changes “Person with diabetes” vs. “diabetic” 2016 FIESTA “Person with diabetes” vs. “diabetic” Support technology to assist diabetes management Obesity management/treatment recommendations Cefalu WT. Diabetes Care 2016;29(1):S1-S112.

Testing All adults ≥45 years old regardless of weight 2016 FIESTA All adults ≥45 years old regardless of weight Any person who is overweight/obese with ≥1 risk factor Cefalu WT. Diabetes Care 2016;29(1):S1-S112.

Diabetes Management in Pregnancy 2016 FIESTA A1c target 6-6.5% instead of 6% Insulin or metformin > glyburide Cefalu WT. Diabetes Care 2016;29(1):S1-S112.

2016 FIESTA

New Diabetes Therapies DPP-4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors New Basal Insulins New Bolus Insulins

Where do diabetes meds work? 2016 FIESTA Brain Liver ↑ satiety ↓ glucose production Pramlintide Incretin mimetics Insulin Metformin TZDs Pramlintide DPP-4 inh. Incretin mimetics Muscle and Adipose ↑ peripheral glucose uptake Insulin Metformin TZDs Pancreas Intestines ↓ digestion and absorption of carbs ↑ insulin secretion Insulin Sulfonylureas Meglitinides DPP-4 inh. Incretin mimetics Metformin a-glucosidase inh. Kidneys Delay gastric emptying ↓ glucose reabsorption Pramlintide Incretin mimetics SGLT2 inhibitor

What level do they fix? FASTING MIXED POSTPRANDIAL Metformin SU 2016 FIESTA FASTING MIXED POSTPRANDIAL Metformin SU Regular insulin Rapid insulins TZDs Incretin mimetics Meglitinides Interm. insulin Long insulin a-glucosidase (-) DPP-4 (-) SGLT2 (-) Incretin mimetics (Exen.) Pramlintide

Incretin Effect Eat food  nutrients and glucose in the gut 2016 FIESTA Eat food  nutrients and glucose in the gut Intestinal mucosal cells sense this and release hormones called incretins GLP1 = glucagon like peptide 1 GIP = glucose-dependent insulinotropic polypeptide The “incretin effect” is decreased in type 2 diabetes, so we need to replace levels. Idris I. Diabetes Obes Metab 2007;9:153-65.

Need for Drug Therapy That: 2016 FIESTA Inhibits degradation of DPP-4 so there is more circulating incretin; DPP-4 inhibitors OR Replaces incretin altogether by giving an analog exogenously Incretin mimetic, or GLP-1 receptor agonist

Dipeptidyl Peptidase - 4 (DPP-4) Inhibitors 2016 FIESTA Dipeptidyl Peptidase - 4 (DPP-4) Inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) + Metformin (Janumet, XR) + Simvastatin (Juvisync) + Metformin (Kombiglyze XR) Linagliptin (Tradjenta) Alogliptin (Nesina) + Metformin (Jentadueto) + Empagliflozin (Glyxambi) + Metformin (Kazano) + Pioglitazone (Oseni) Lexi-complete Online. Accessed 4/7/16.

DPP-4 Inhibitors Mechanism: 2016 FIESTA Mechanism: Inhibits DPP-4 (enzyme that breaks down incretin)  Increased circulating incretin, helping control glucose absorbed in the diet Glucose-dependent increase in insulin secretion Glucose-dependent inhibition of glucagon secretion Idris I. Diabetes Obes Metab 2007;9:153-65. Drucker DJ. Lancet 2006;368:1696-705.

DPP-4 Inhibitors - Safety 2016 FIESTA Adverse Effects: Placebo-like: HA, URI, nasopharyngitis, UTI Rare: pancreatitis, skin reactions, urticaria/angioedema Contraindicated: Hx of pancreatitis, DKA, type 1 diabetes Counseling: With or without food Lexi-complete Online. Accessed 4/7/16.

DPP-4 Inhibitors - Efficacy 2016 FIESTA Average A1c reduction: 0.6-0.8% Primarily acts on postprandial glucose Remember they are glucose-dependent

DPP-4 Inhibitors Advantages: Disadvantages: 2016 FIESTA Advantages: No hypoglycemia as monotherapy Weight neutral Placebo-like Adverse effects Beta cell preservation Linagliptin – no renal adjustments needed Disadvantages: Modest A1c lowering Cost Long term safety unknown

DPP-4 Inhibitors Dosing Guide 2016 FIESTA Sitagliptin 100mg po daily CrCl 30-49= 50mg po daily CrCl ≤ 30= 25mg po daily ESRD= 25mg po daily without regard to HD Reduce dose of concomitant insulin/secretagogues Saxagliptin 2.5 – 5mg po daily CrCl ≤ 50 = 2.5mg po daily ESRD = 2.5mg po daily, post-HD With strong CYP 3A4/5 inhibitors (“conazoles” and protease inhibitors) = 2.5mg po daily Lexi-complete Online. Accessed 4/7/16.

DPP-4 Inhibitors Dosing Guide 2016 FIESTA Linagliptin 5mg po daily Reduce dose of concomitant insulin/secretagogues No renal dose adjustment needed Alogliptin 25mg po daily CrCl 30-59= 12.5mg po daily CrCl 15-29= 6.25mg po daily ESRD= 6.25mg po daily, without regard to HD Lexi-complete Online. Accessed 4/7/16.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Exenatide (Byetta, Bydureon) Liraglutide (Victoza, Saxenda) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Lixisenatide (Lyxumia) App. for new drug approval submitted 9/2015 Lexi-complete Online. Accessed 4/7/16. FDA Drugs. Accessed 4/11/16.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Mechanism: GLP1 analog Increases incretin levels Glucose-dependent increase in insulin secretion Glucose-dependent inhibition of glucagon Reduces gastric emptying Increases satiety Lexi-complete Online. Accessed 4/7/16.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Adverse Effects: Nausea – 8-40% more vs. placebo/comparator Exen BID>Lira>Exen Q7D>Alb/Dula Diarrhea – 3-118% more vs. placebo/comparator Rare – pancreatitis, renal dysfunction, thyroid tumors CI: Gastroparesis Pancreatitis Exen: CrCl <30 (maybe others?) Lira, Alb, Dula, Exen: PMH or FH of thyroid cancer, multiple endocrine neoplasia Shyangdan DS. Cochrane Database Syst Rev 2011. Lexi-complete Online. Accessed 4/7/16.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Efficacy: A1c reduction 1-2% Adjunct for type 2 diabetes BID = More postprandial reduction Daily, Q7D Dosing = More fasting reduction Drucker DJ. Lancet 2006;368:1696-705. Lexi-complete Online. Accessed 4/7/16.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Dosing considerations Inject into thigh, abdomen, upper arm Exenatide BID 60 minutes prior to 2 main meals Reduce incidence of nausea with proper dose titration (start low, go slow) Once-weekly injections < twice daily injections Lexi-complete Online. Accessed 4/7/16.

Exenatide IR to ER Start weekly dose the day after D/C IR 2016 FIESTA Start weekly dose the day after D/C IR D/C IR Monday, start ER Tuesday Pt may have increased BG levels for 2 weeks Pretreatment for this temporary rise is unnecessary Lexi-complete Online. Accessed 4/7/16.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Advantages: Weight loss – 1-5kg No priming after initial dose Extended release option available Preservation of beta cell function Decrease insulin resistance Shyangdan DS. Cochrane Database Syst Rev 2011.

GLP 1 Receptor Agonists (a.k.a. incretin mimetics) 2016 FIESTA Disadvantages: May reduce absorption rate and extent of drugs requiring rapid absorption (i.e. pain relievers, antibiotics, BCPs). Separate by 1 hour. Requires subcutaneous injection Cost GI side effects Lexi-complete Online. Accessed 4/7/16.

GLP-1 Agonists Dosing Guide 2016 FIESTA Byetta (exenatide) 5mcg subq BID ac, increase to 10mcg subq BID after 1 month CrCl <30= use is not recommended Bydureon (exenatide) 2mg subq once weekly Victoza (liraglutide) 0.6 mg subq once daily x 1 week, then increase to 1.2mg subq once daily. May go to 1.8mg if optimal glycemic response not achieved. If missed doses, resume with next scheduled dose. If >3 days of missed doses, resume with 0.6mg dose and retitrate. No CrCl limitations on use Lexi-complete Online. Accessed 4/7/16.

GLP-1 Agonists Dosing Guide 2016 FIESTA Tanzeum (albiglutide) 30mg subq once weekly, may increase to 50mg once weekly if inadequate response at week 12. Missed dose = administer ASAP within 3 days. If >3 days have passed, omit dose and resume with next scheduled dose. No renal adjustment necessary. Trulicity (dulaglutide ) 0.75mg subq once weekly; may increase to 1.5mg weekly if inadequate response. Same missed dose regimen as albiglutide Lyxumia (lixisenatide) – once daily prandial subq injection, dose TBA Lexi-complete Online. Accessed 4/7/16.

Incretin Mimetic vs. DPP-4 Inhibitors 2016 FIESTA Incretin Mimetic DPP-4 Inhibitor Delay gastric emptying No effect on gastric emptying Increase satiety No increase in satiety Lots of N/V Placebo-like adverse rxn. Weight loss No change in weight SC administration PO administration Drucker DJ. Lancet 2006;368:1696-705.

SGLT2 Inhibitors Canagliflozin (Invokana) Dapagliflozin (Farxiga) 2016 FIESTA Canagliflozin (Invokana) Dapagliflozin (Farxiga) Approved 3/13 + Metformin (Invokamet) Approved 1/14 + Metformin (Xigduo) Empagliflozin (Jardiance) Approved 8/14 + Metformin (Synjardy) + Linagliptin (Glyxambi) Lexi-complete Online. Accessed 4/7/16.

SGLT2 Inhibitors Mechanism of Action 2016 FIESTA Blocks renal absorption of ~90% of excess glucose, promotes urinary glucose excretion. Highly selective inhibitor of sodium glucose cotransporter 2 Causes renal wasting of glucose, lowering serum BG and A1c over time Minimizes chance of hypoglycemia Jurczak MJ. Diabetes 2011;60:890-8. Lexi-complete Online. Accessed 4/7/16.

SGLT2 Inhibitors Adverse Effects: Contraindications: 2016 FIESTA Adverse Effects: Urinary/genital infections Hypotension Bone fractures DKA Hyperkalemia Renal insufficiency Contraindications: Hypersensitivity ESRD/Dialysis Lexi-complete Online. Accessed 4/7/16.

SGLT2 Inhibitors Counseling Points: Efficacy With or without food 2016 FIESTA Counseling Points: With or without food Before the first meal of the day Efficacy 0.5-0.9% A1c lowering Mostly post-prandial glucose lowering Lexi-complete Online. Accessed 4/7/16.

SGLT2 Inhibitors Advantages: Disadvantages: 2016 FIESTA Advantages: New mechanism, another option Less hypoglycemia Weight loss Potential BP-lowering Disadvantages: DKA Price / insurance coverage May encourage diet indiscretions? Cancer risk?

Dosing Recommendations 2016 FIESTA Canagliflozin (Invokana) 100mg po once daily before first meal of the day eGFR 45-59 = 100mg po daily max eGFR <45 = use is not recommended/Contraindicated Dapagliflozin (Forxiga) 10 mg po once daily without regard to meals eGFR <60 = use is not recommended/Contraindicated Empagliflozin (Jardiance) 10mg po once daily without regard to meals Lexi-complete Online. Accessed 4/7/16.

Type 2 Therapies (Fig 7.1) 2016 FIESTA Cefalu WT. Diabetes Care 2016;29(1):S1-S112.

New Insulin Therapies

New Insulin Therapies Ideal basal insulin Bolus insulin Peakless 2016 FIESTA Ideal basal insulin Peakless Consistent rate of absorption No weight gain True 24-hour coverage Bolus insulin Lots of injections Titratable dose Minimize side effects 1. Insulin degludec (Tresiba) 2. Insulin glargine (Toujeo) 3. Insulin glargine (Basaglar) 4. Humalog U-200 KwikPen 5. Inhaled insulin (Afrezza) Hess R. ACSAP 2016;1:35-64.

Insulin degludec (Tresiba) 1 Insulin degludec (Tresiba) 2016 FIESTA Image: https://www.diabetesdaily.com/blog/2015/09/tresiba-fda-approves-new-basal-insulin-in-the-usa/. Accessed 4/11/16.

Insulin degludec (Tresiba) 2016 FIESTA Long-acting insulin Onset = 1 hour Time to peak = 9 hours t ½ = 25 hours Duration = 42 hours Lexi-complete Online. Accessed 4/7/16.

Insulin degludec Mechanism 2016 FIESTA Naturally, insulin dimers form hexameric complexes to maximize storage within beta-cell vesicles Degludec mimics this natural process Hexamer  multihexameric chain = depot formation with a slow constant release over time Jonassen I. Pharm Res 2012;29:2104-14.

Head-to-Head: Insulin degludec vs. 2016 FIESTA Insulin glargine Noninferiority criteria met (95% CI -0.14 to 0.11) Nocturnal hypoglycemia rates 25% lower (p=0.021) Mean weight gain similar (1.8 kg with degludec and 1.6 kg with glargine) (p=0.62) Insulin detemir (+ aspart) Noninferiority criteria met (95% CI -0.23 to 0.05) Nocturnal hypoglycemia 34% lower (p=0.0049) Weight gain higher with degludec (est. diff. 1.08 kg; p<0.0001) Heller S. Lancet 2012;379:1489-97. (BEGIN) Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1)

HbA1c Comparison 2016 FIESTA Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1)

Insulin degludec (Tresiba) 2016 FIESTA 100 units/mL and 200 units/mL available No conversion calculation necessary; same unit per unit dose Dosing: Type 1: 0.2-0.4 units/kg (1/3-1/2 the TDD) Type 2: 10 units once daily Missed doses: administer ASAP to ensure at least 8 hours between doses Stable at room temp for 8 weeks Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1) Lexi-complete Online. Accessed 4/7/16.

Insulin glargine (Toujeo) 2 Insulin glargine (Toujeo) 2016 FIESTA Image: https://www.toujeo.com. Accessed 4/7/16.

Insulin glargine (Toujeo) 2016 FIESTA No change in physiological mechanism Smaller amount of depot insulin Smaller surface area More gradual and prolonged release of hexamers Smaller amount of liquid per unit 450 units (300 u/mL) vs. 300 units (100 u/mL) in Lantus pen Home PD. Am Diabetes Assoc 2014;2014:abstract 80-LB.

Head-to-Head: Toujeo vs. Lantus 2016 FIESTA Noninferiority met at 26 weeks (95% CI 0.1-0.19) Nocturnal hypoglycemia 31% lower in first 8 weeks (CI 0.53-0.91) No difference at 26 weeks Less weight gain (est. diff. 0.5 kg, p=0.037) Home PD. Am Diabetes Assoc 2014;2014:abstract 80-LB.

Basaglar (insulin glargine) 3 Basaglar (insulin glargine) 2016 FIESTA Eli Lilly/Boerhinger Ingelheim. Introducing: Basaglar. https://www.basaglar.com/# (accessed 4/7/16).

Basaglar (insulin glargine) 2016 FIESTA Lilly/BI’s answer to Sanofi-Aventis’s Lantus Same PK profile, not interchangeable Approved for use in type 1 kids and adults, and type 2 adults Available starting 12/2016 Blevins TC. Diabetes Obes Metab 2015;17:726-33. (ELEMENT 1) Eli Lilly/Boerhinger Ingelheim. Introducing: Basaglar. https://www.basaglar.com/# (accessed 4/7/16).

Head-to-Head: Basaglar vs. Lantus 2016 FIESTA Noninferiority met at 24 weeks 95% CI -0.002 to 0.219 Symptomatic and nocturnal hypoglycemia similar Weight gain similar 0.36 kg Basaglar vs. 0.12 kg Lantus Insulin antibodies similar Blevins TC. Diabetes Obes Metab 2015;17:726-33. (ELEMENT 1)

4 Humalog U-200 KwikPen 2016 FIESTA Image: http://www.ulticare.com/pen-needles/. Accessed 4/11/16.

Humalog U-200 KwikPen 200 units/ml 2016 FIESTA 200 units/ml 600 units/pen (versus 300 units/pen) Good for patients who go through 2 or more mealtime insulin pens each month Lexi-complete Online. Accessed 4/7/16.

Inhaled insulin (Afrezza) 5 Inhaled insulin (Afrezza) 2016 FIESTA Images: Afrezza. https://www.afrezza.com/hcp

Inhaled insulin (Afrezza) 2016 FIESTA “Technosphere insulin” Helps reduce injection barriers to therapy Lungs have a large surface area and high bioavailability New inhaler device called “Dreamboat” Replace every 15 days Insulin cartridges available: 4 units, 8 units, 12 units Concerns: pulmonary toxicity/malignancy Lexi-complete Online. Accessed 4/7/16. Bode BW. Diabetes Care 2015;38:2266-73. Raskin P. Diabetes Obes Metab 2012;14:163-73.

Head-to-Head: Inhaled insulin vs. aspart 2016 FIESTA Mean change in HbA1c noninferior More aspart patients achieved HbA1c <7.0% (30.7% vs. 18.3%) Inhaled insulin had less hypoglycemia (9.8 vs 14.0 events/patient-month, p<0.0001) Inhaled insulin patients experienced weight loss (-0.4 kg) vs. gain (+0.9 kg) for aspart patients (p=0.0102) Most frequent AE = cough which led to discontinuation in 5.7% of patients Bode BW. Diabetes Care 2015;38:2266-73.

Dosing Chart Configurations 2016 FIESTA Afrezza. https://www.afrezza.com/AfrezzaConfigurationChart.pdf

Diabetes Meds in the Pipeline 2016 FIESTA Novo Nordisk Xultophy (insulin degludec + liraglutide) Faster-acting insulin aspart Semaglutide (oral and injectable) Eli Lilly BioChaperone insulin lispro R&D Pipeline. http://www.novonordisk.com/rnd/rd-pipeline.html. Accessed 4/11/16. Anderson G. Diabetes 2014;63(suppl 1).

FIESTA 2016 : ACCRA GHANA 2016 FIESTA THANK YOU?? MEDA MO ASE PII

2016 FIESTA

Innovative Care Solutions and Ideas Patient Assistance Programs Coupons Medication Pricing Apps Medication Lists

Patient Assistance Programs (PAPs) 2016 FIESTA Provided by pharmaceutical companies To provide brand-name medications For low-income individuals who lack prescription drug coverage Vs. coupon, sample, 340B, drug card, bulk replacement programs, and Medicare Part D Advocate “PAPs are a long term solution to a current medication access problem” Am J Health-Syst Pharm. 2006; 63:1254-9. Sagall RJ. Pharmaceutical companies helping patients get their medications. Accessed at http://www.needymeds.org/indices/article.htm on 2/21/13.

Programs Available NeedyMeds Partnership for Prescription Assistance 2016 FIESTA NeedyMeds http://www.needymeds.org Partnership for Prescription Assistance http://www.pparx.org RxAssist http://www.rxassist.org TogetherRx Access http://www.togetherrxaccess.com National Council on Patient Information and Education http://www.talkaboutrx.org Manufacturers’ websites

Finding an application 2016 FIESTA Medications covered Type (brand, generic) Insurance status Private insurance Medicare Part D (coverage gap) No insurance

Coupons Discount the price of medications for a set number of fills 2016 FIESTA Discount the price of medications for a set number of fills Search patient assistance websites for coupons Hard copy cards at physician offices from drug company representatives

Medication Pricing - GoodRx 2016 FIESTA Losartan 50mg #30 Wal-Mart pricing by phone = $39.41 Price obtained by phone from Wal-Mart Neighborhood Market, 4404 S. Peoria Ave. Tulsa, OK on 4/11/16.

Medication Pricing - GoodRx 2016 FIESTA Screenshots taken 4/7/16.

Medication Pricing - GoodRx 2016 FIESTA Screenshots taken 4/7/16.

Medication Lists 2016 FIESTA MyMedSchedule.com

Medication Lists My Medicine List http://www.safemedication.com 2016 FIESTA My Medicine List http://www.safemedication.com

Questions?

Diabetes Update 2016: New Drugs and New Methods of Care Kelly Murray, PharmD, BCACP Clinical Assistant Professor of Clinical Pharmacy OSU College of Osteopathic Medicine Emergency Department Clinical Pharmacist OSU Medical Center