2018 Diabetes Pharmacotherapy Overview

Susan Cornell, BS, PharmD, CDE, FAPhA, FAADE

Associate Professor Midwestern University ‐ Chicago College of Pharmacy Objectives

• Describe recent updates in the pharmacotherapy management recommendations for type 2 diabetes.

• Discuss the rationale regarding therapeutic decision making when adding on to, or replacing metformin in type 2 diabetes.

• Assess the appropriateness of SGLT‐2 inhibitors, DPP‐4 inhibitors, GLP‐1 agonists, and newer concentrated insulins based on specific patient characteristics. Metformin is CURRENTLY most commonly used as “first line” therapy.

What is the reason for that? 1) Decreases liver Biguanides (Metformin) glucose production 2) indirectly reduces GI tract - insulin resistance microbiome 3) Possible restoration Islet b-cell of gut microbiome Impaired Insulin Secretion ? Increased Lipolysis

Islet a-cell

Increased Glucagon Secretion Increased Glucose Reabsorption

Increased Decreased Glucose Hepatic Glucose Uptake Production Neurotransmitter Dysfunction

DeFronzo RA. Diabetes. 2009;58(4):773-795. Tips for Use: Metformin • Dosing – Metformin immediate release • Start with 500mg daily to BID • Max effective dose is 2000mg/day • Individualize titration based on GI side effects – Metformin XR • May be helpful if immediate release GI effects are bothersome • Start XR 500mg – XR 750mg QD

– Take with food to reduce GI side effects – Ideally take in evening/bedtime – Monitor: A1C, Serum Creatinine, eGFR, B12 levels Metformin

• Historically, serum creatinine was the measure used to determine if a patient could be prescribed metformin. • More recent studies support the use of the glomerular filtration rate estimating equation (eGFR).

General Practice Recommendations eGFR 45 – 60 Continue therapy, ml/min monitor renal function every 3 – 6 months eGFR 30 – 45 Avoid initiation of metformin ml/min If already using, consider dose adjustment to max of 500mg BID eGFR < 30 Do not use / discontinue use Ml/min

Diabetes Guidelines, Endocr Pract. 2015;21(Suppl 1), Diabetes Care 2017;40(Suppl. 1):S57‐S634 http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm accessed 4/13/17 What comes after metformin?

How do you choose a second agent? Clinical Inertia Leaves Patients Unnecessarily Exposed to Hyperglycemia

Median Time to Addition of Another OAD or Insulin

Patients taking 1 OAD 2.2 y; mean A1c: 8.7%

Patients taking 2 OADs > 7.2 y*; mean HbA1c : 9.1%

Patients taking 3 OADs > 7.1 y*; mean HbA1c : 9.7%

0 1 2 3 4 5 6 7 8 Time, y

*Indicates that < 50% of subjects have intensified treatment. Mean time between HbA1c measurements was 6.2 to 7 months. Khunti K, et al. Diabetes Care. 2013;36:3411‐3417. 12 Pharmacotherapy Options

Insulin (1) . Oral Medications (9) . Bolus insulin – -glucosidase inhibitors (AGI) – Insulin lispro – Biguanides • U100 – Bile acid sequestrants (BAS) • U200 – Dipeptidyl peptidase-4 (DPP-4) – Insulin aspart inhibitors (gliptins) – Insulin glulisine – Dopamine agonists – Insulin human inhaled – Glinides – Regular human insulin – Sulfonylureas (SU) – Sodium Glucose Co-Transporter-2 . Basal insulin inhibitors (SGLT-2i) – Insulin NPH – Thiazolidinediones (TZDs or glitazones) – Insulin detemir – Insulin degludec . Non-insulin injectable agents (2) • U100 – Glucagon-like peptide-1 (GLP-1) • U200 agonists – Insulin glargine – Amylinomimetic • U100 • U300 Cornell S et al. Postgrad Med. 2012;124:84-94. www.pdr.net (accessed 2016 June 30). . ADA/EASD Treatment Guidelines Oct 2018

Davies MJ, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. Publish Ahead of Print, online Oct 4, 2018. Considerations in Drug Selection

• Patient factors to consider – Synergistic / complimentary mechanism of action – A1c lowering needed • Fasting, post‐prandial – Weight/Obesity • High levels of insulin resistance – Cardiovascular disease • Hypoglycemia – Ease of medication administration • Side effect profile – Renal impairment – Cost, available medication coverage 1) ↓ renal glucose reabsorpon SGLT‐2 Inhibitors in proximal tubule of kidney GI Tract/ Decreased Incretin 2) Some ↓ in body fat (possibly Effect due to SGLT‐1 inhibition) Islet b‐cell

Impaired Insulin Secretion Increased ? Lipolysis

Islet a‐cell

Increased Glucagon Secretion Increased Glucose Reabsorption

Increased Decreased Glucose Hepatic Glucose Production Uptake Neurotransmitter Dysfunction

DeFronzo RA. Diabetes. 2009;58(4):773-795. ADA/EASD Treatment Guidelines

Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Efficacy (A1c lowering) Monotherapy ↓ 0.77 ‐ 1.03% ↓ 0.8 – 0.9% ↓ 0.7 – 0.8% ↓ 0.7 – 0.8% Combination ↓ 0.79 ‐ 0.94% ↓ 0.7 – 0.8% ↓ 0.7 – 0.8% ↓ 0.7 – 0.9% Dose and Frequency 100‐300 mg 5‐10 mg 10‐25 mg 5‐15 mg once daily once daily once daily once daily Renal dose adjustment Reduce dose if: eGFR 45‐59: Not recommended No Not 100 mg daily if eGFR 30‐60 recommendation recommended if eGFR 30‐60 Contraindicated eGFR <45ml/min eGFR <30ml/min eGFR <30ml/min eGFR <30ml/min if:

American Diabetes Association (ADA). Diabetes Care. 2018;41(Suppl 1):S1. Package Insert: Steglatro. https://www.steglatro.com SGLT‐2 inhibitors

• Most common side effects ‐Weight loss ‐ Vaginal and male genital infections ‐Rash ‐UTI ‐ Frequent urination ‐ Increased thirst ‐ GI problems (when combined with metformin or GLP‐1 agonist)

List JF, et al. Diabetes Care. 2009;32(4):650-657. Wilding JP, et al. Diabetes Care. 2009;32(9):1656-1662. Tips for Use

• Educate patients on proper GU hygiene, importance of hydration, signs/symptoms of DKA, increase frequency of urination • Use caution in patient on volume depleting drugs (e.g diuretics) • Good combination with: – Metformin – DPP‐4i – GLP‐1 agonist The Next Generation of SGLT2 Inhibitors Dual SGLT1/SGLT2 Inhibitor

Sotagliflozin (LX4211) for type 1 and type 2 diabetes

SGLT1 is a transporter responsible for glucose and galactose absorption in the GI tract and glucose reabsorption in the kidneys (though to a lesser extent than SGLT‐2)

PCT = proximal convoluted tubule; PST = proximal straight tubule Dual SGLT1/SGLT2 Inhibitor

• Sotagliflozin as adjunct to insulin in T1DM • Randomized, double-blind trial to assess: – Safety – Insulin dose – Glycemic control

• Dual SGLT1 & SGLT2 inhibition with sotagliflozin: – Improved glycemic control – Reduced bolus insulin dose – Weight loss – No increased hypoglycemia

Sands AT, et al. Diabetes Care. 2015;38:1181-1188 Sotagliflozin As Adjunct Therapy to Insulin in Type 1 Diabetes

Placebo P Efficacy and Safety Sotagliflozin (N = 17) (N = 16)

HbA1c change from baseline (%) −0.06 −0.55 0.002 FPG change from baseline assessed at day 29 (mg/dL) 39.0 −18.6 0.15 Daily bolus insulin change from baseline assessed at days 3–27 (%) −6.4 −32.0 0.007 Daily basal insulin change from baseline assessed at days 3–27 (%) 0.2 −2.4 0.53 Total daily insulin change from baseline assessed at days 3–27 (%) −0.7 −15.3 0.029 Mean body weight change from baseline assessed at day 29 (kg) 0.5−1.70.005 Seated systolic blood pressure change from baseline assessed at day 29 −3.9 −4.9 0.45 (mmHg) Patients with serious adverse effects (both with DKA) 0 2 N/A Hypoglycemic events (SMBG ≤70 mg/dL, baseline–day 36) 354 304 N/A Documented symptomatic hypoglycemia (SMBG ≤70 mg/dL, baseline–day 185 162 N/A 36)

Sands AT, et al. Diabetes Care. 2015;38:1181-1188 1) Enhances appropriate GLP‐1 Agonists GI Tract/ pancreatic beta cell (insulin Decreased and amylin) secretion Incretin Effect

Increased 2) Pancreatic alpha cell Impaired Islet b‐cell Lipolysis (glucagon) suppression Insulin Secretion 3) ↓ liver glucose producon 4) ↑ brain saety 5) slows gastric emptying time Increased Glucagon Secretion 6) ↑ insulin uptake in peripheral Islet a‐cell tissue via weight loss

Increased Glucose Reabsorption

Increased Hepatic Glucose Decreased Glucose Production Uptake

Neurotransmitter Dysfunction

DeFronzo RA. Diabetes. 2009;58(4):773-795. ADA/EASD Treatment Guidelines

Exenatide BID Lixisenatide Liraglutide Exenatide QW Dulaglutide Semaglutide

Short‐acting Short‐acting Long‐acting Long‐acting Long‐acting Long‐acting Twice daily Once daily Once daily Once weekly Once weekly Once weekly Dose 5 & 10 mcg 10 & 20 mcg 0.6, 1.2 & 1.8 mg 2 mg 0.75 & 1.5 mg 0.25, 0.5 & 1.0 mg within 30‐60 within 60 min of 0.6mg initially 0.25 mg initially min of am/pm same meal then ↑ to 1.2 mg. then ↑ to 0.5mg meal Can ↑ to 1.8 mg if Can ↑ to 1.0 mg needed if needed Max dose 10mcg BID 20mcg daily 1.8mg daily 2mg weekly 1.5mg weekly 1.0mg weekly Half‐ life 2‐4 hours 2‐4 hours 13 hours 5 days 5 days 7 days Homology 53% 50% 97% 53% 90% 94% to GLP‐1 Antibodies 44% 69.8% 8.6% 44% 2% 1%

Renal dosing: < 15 <30 avoid <30 No (eGFR ‐ not not No adjustment No adjustment 15–59 adjustment mL/min/1.73 recommended use caution and recommended m2) monitor

Byetta®. Bydureon®. Prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP. Victoza®. Ozempic®. Prescribing information. Plainsboro, NJ: Novo Nordisk Inc. Trulicity® Prescribing information. Indianapolis, IN: Eli Lilly and Company. Adlyxin® Prescribing information. Sanofi-US, LLC. Tips for Use

• Educate and monitor injection technique • Discuss/prepare patient on how to minimize nausea, GI side effects • Caution in patients at risk for pancreatitis • Good combination with: – Metformin – TZD – SGLT‐2i – Basal insulin 1) Inhibits DPP‐4 enzyme in the DPP4 Inhibitors (Gliptins) Decreased GI tract that breaks down Incretin GLP‐1 resulng in ↑ Effect endogenous GLP‐1.

Increased Lipolysis 2) Enhances appropriate Islet b‐cell pancreatic beta cell (insulin Impaired and amylin) secretion Insulin Secretion 3) Pancreatic alpha cell (glucagon) suppression 4) ↓ liver glucose production Islet a‐cell

Increased Increased Glucose Glucagon Secretion Reabsorption

Increased Neurotransmitter Dysfunction Hepatic Glucose Production Decreased Glucose Uptake

DeFronzo RA. Diabetes. 2009;58(4):773-795. ADA/EASD Treatment Guidelines

sitagliptin saxagliptin linagliptin alogliptin Dose/ 100 mg 5 mg 5 mg 25 mg frequency once daily once daily once daily once daily Efficacy (A1C lowering): monotherapy  0.6%  0.7%  0.4%  0.8%

Efficacy (A1C lowering): combination therapy  0.7%  1.2%  0.7%  0.9%

50 mg daily 12.5 mg daily **No dose (moderate) 2.5 mg daily (moderate) Renal dosing adjustment 25 mg daily (moderate‐severe) 6.25 mg daily necessary (severe) (severe) Approximate ex Vivo DPP‐4 Inhibition, % 97 80 80 90 (maximum)

Baetta R. Drugs 2011;71:1441‐1467, Deacon. Diabetes Obes Metab. 2011;13:7–18. Januvia® (sitagliptin). Prescribing information.. Onglyza® (saxagliptin). Prescribing information. Tradjenta® (linagliptin). Prescribing information. Nesina™ (alogliptin). Prescribing information Tips for Use

• Best used for patient with A1c near normal – Minimal A1c lowering – PPG target • Minimal side effects • Stuffy, runny nose • Headache • Upper respiratory tract infection • Good combination with: – Metformin – SGLT‐2i Sulfonylureas 1. Stimulates pancreatic beta cell (insulin) secretion

GI tract/ Decreased Incretin Islet b‐cell Effect

Increased Impaired Lipolysis Insulin Secretion

Islet a‐cell

Increased Glucose Increased Reabsorption Glucagon Secretion

Increased Decreased Glucose Hepatic Glucose Production Uptake Neurotransmitter Dysfunction Tips for Use

• Take in morning before/with breakfast • If dosed BID, take with breakfast and supper. – Patient should check bedtime BG and have snack if needed • Patients need to eat on schedule – Do not skip meals/snacks • Risk of hypo • Most common side effects • Hypoglycemia • Weight gain • may inhibit ischemic pre‐conditioning ADA/EASD Treatment Guidelines

TZD’s 2) ↑ free fay acid ulizaon (conversion of bad fat to good fat)

GI tract/ Decreased Incretin Islet b‐cell Effect

Increased Impaired Lipolysis Insulin Secretion

Islet a‐cell

Increased Glucose Increased Reabsorption Glucagon Secretion

Increased Decreased Glucose Hepatic Glucose Production Uptake Neurotransmitter Dysfunction Tips for Use • Takes 4‐8 weeks before effect is noticed. – Patients need to give TZD’s 2‐3 months use • Best used early in the disease process • Most common side effects • Edema (swelling) usually in the legs • Weight gain • Possible ↑ risk of fractures. • Good combination with: – GLP‐1 agonists – Metformin – SGLT‐2i (?) 1) Mimics pancreatic beta cell Insulin (insulin) secretion 2) Pancreatic alpha cell GI Tract/ (glucagon) suppression Decreased Increased Incretin Lipolysis Effect 3) ↓ liver glucose producon Impaired Islet b‐cell Insulin Secretion 4) ↑ insulin uptake in peripheral tissue

5) ↑ free fay acid ulizaon

Increased Glucagon Secretion Islet a‐cell

Increased Glucose Reabsorption

Increased Hepatic Glucose Production

Neurotransmitter Dysfunction Decreased Glucose Uptake

DeFronzo RA. Diabetes. 2009;58(4):773-795. ADA/EASD Treatment Guidelines

Intermediate (NPH insulin) Long (Insulin detemir) Ultralong degludec Long (Insulin glargine) U100, U200 Ultralong (glargine U300) Plasma Insulin Levels

021418224 6 8 10 1216202426 28 30 32 34 36 Time (h) Fixed Combination Products

Insulin glargine + lixisenatide (Soliqua™) – iGlarLixi

Insulin degludec + liraglutide (Xultophy®) ‐ iDegLira

Image available at: http://www.pharmasay.com/2016/12/12/insulin‐soliqua‐10033‐glargine‐lixisenatide‐available‐january‐2017/ Image available at: https://www.diabetesdaily.com/blog/fda‐approves‐novo‐nordisks‐xultophy‐combination‐drug‐for‐type‐2‐diabetes‐322527/ Insulin + GLP‐1 agonist GI Tract/ GLP‐1 Decreased Insulin Incretin Insulin Islet b‐cell Effect GLP‐1

Increased Impaired Lipolysis Insulin Secretion

Islet a‐cell Insulin GLP‐1

Increased Glucose Increased Reabsorption Glucagon Secretion Insulin Insulin GLP‐1 GLP‐1 GLP‐1 Decreased Glucose Increased Uptake Hepatic Glucose Production Neurotransmitter Dysfunction Official Name Xultophy (Degludec 100 units/mL Soliqua (Glargine 100 units/mL Components Liraglutide 3.6 mg/mL) Lixisenatide 33 mcg/mL) 1 Dosing Unit= 1 Dosing Unit= Ratio Degludec U‐100 1Unit/ Glargine U‐100 1 Unit/ Liraglutide 0.036mg Lixisenatide 0.33 mcg

Maximum Dose 50 UNITS 60 UNITS Start at 16 UNITS for All Conversions 15 UNITS if: <30 units basal insulin Conversion from Lixisenatide Starting Dose 30 UNITS if: Convert from 30‐60 units basal insulin Prime before every use Prime before every use Priming

Not Basal insulin dose >50 units Basal insulin dose >60units recommended Delivery/Adjust Pen Device Daily Dosing/3‐4 days Pen Device Daily Dosing/weekly Weight Considerations

Gain Neutral Loss SU Metformin GLP‐1 agonist Meglitinides DPP‐4 inhibitor SGLT‐2 inhibitor Insulin AG inhibitor Amylin mimetic TZD Bile acid sequestrants Dopamine agonist

Cornell S, D’Souza J. Postgrad Med 2014; 126 (2): 100‐109. Combination & Co‐formulation Considerations Brand Name Glyburide Glucovance Glipizide Metaglip Repaglinide PrandiMet Pioglitazone Actoplus Met Rosiglitazone Avandamet Sitagliptin Janumet or XR Metformin + Saxagliptin Kombiglyze XR Alogliptin Kazano Linagliptin Jentadueto or XR Empagliflozin Synjardy or XR Canagliflozin Invokamet or XR Dapagliflozin Xigduo XR Ertugliflozin Stegluromet Brand Name Pioglitazone Glimepiride Duetact Rosiglitazone Glimepiride Avandryl Pioglitazone Alogliptin Oseni Empagliflozin Linagliptin Glyxambi Dapagliflozin Saxagliptin Qtern Ertugliflozin Sitagliptin Steglujan Insulin glargine U‐100 Lixisenatide Soliqua Insulin degludec U‐100 Liraglutide Xultophy Do NOT Use Combinations

• Duplicate Mechanisms of Action • Sulfonylurea + meglitinide

• GLP‐1 agonist + DPP4 inhibitor

• 2 long acting/intermediate insulins

• 2 rapid/short acting insulins

• Sulfonylurea/meglitinide + rapid/short acting insulin Effective Metformin Combinations

• Need FPG lowering • Need PPG lowering – Met + SU – Met + DPP‐4i – Met + TZD – Met + SGLT‐2i – Met + SGLT‐2i – Met + GLP‐1 agonist – Met + GLP‐1 agonist (short) (long) – Met + Basal Effective Non‐Met Combinations

• Modest A1c reduction (primarily PPG) – DPP‐4i + SGLT‐2i

• High A1c lowering (FPG + PPG) – GLP‐1 agonist + TZD – GLP‐1 agonist + SGLT‐2i – GLP‐1 agonist + Basal insulin Key Points

• Diabetes guidelines encourage individualizing therapy

• Several factors guide drug therapy selection including: – patient safety – cardiovascular benefit – blood glucose lowering potential – weight effects – cost – adherence – patient preferences • Key Points

• Metformin is currently recommended as initial therapy for most patients with type 2 diabetes. – Although, most patients will require additional therapy, particularly as the disease progresses.

• Newer medications offer additional treatment options with other positive effects

• Liraglutide and empagliflozin have cardiovascular benefits. • More data on other (newer) drugs to come soon