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Home , Insulin degludec, Insulin detemir

1/18/2016

What’s New in Type 2 OBJECTIVES •Describe the most recent drug approvals for : New Drug including new , DPP-4 Approvals and Treatment inhibitors, GLP-1 agonists, and SGLT2 inhibitors Updates •Describe the 2015 management of hyperglycemia algorithm from the American Gretchen Ray, PharmD, PhC, BCACP, CDE Diabetes Association Associate Professor, UNM College of Pharmacy •Describe updates from the 2016 American Diabetes Association standards of care in January 23, 2016 diabetes

Canagliflozin 2013 UPDATED GUIDELINES DIABETES MEDICATIONS Afrezza inhaled 2014 •Standards of Medical Care in Diabetes 2016. U-300 Glargine Diabetes Care 2016;39(Suppl 1) Basaglar 2011 2015 Insulin •Management of Hyperglycemia in Type 2 1922 AGIs SUs 2006 Diabetes 2015: A Patient Centered Approach. 1995 2009 1957 Diabetes Care 2015; 38:140-49

1960 1995 2000 2005 2010 2015

Glinides TZDs 2010 1997 2005

2012 Exenatide LAR

TYPES OF INSULIN LONG ACTING/BASAL INSULIN • Rapid Acting • Humalog® (lispro) (U-100 and U-200) • Novolog ® (aspart) • Apidra ® (glulisine) (Levemir®) (Lantus®) • Short Acting- (R) • Novolin® R • Once or twice daily • Once daily dosing • Humulin® R • Intermediate Acting-NPH (N) dosing • Pens or vials • Novolin® N • BID dosing usually • U-100 • Humulin ® N needed if dose <0.8 • Long Acting – Basal Insulin • Levemir® (detemir) units/kg • Lantus® (glargine) • Toujeo® (U-300 glargine) • Pens or Vials • Tresiba®(Degludec) • Inhaled Insulin • U-100 • Afrezza: Sanofi just ended contract to sell Afrezza

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INSULIN GLARGINE 300 UNITS/ML (TOUJEO® SOLOSTAR PEN) TOUJEO® VS. LANTUS®

•Higher concentration of Insulin Glargine Pen Volume Package Size Storage of in use pen •Only available in pen form Toujeo® 1.5 mL (450 units) 3 or 5 pens 42 Days Solostar •Same efficacy as Lantus® Lantus® 3 mL (300 units) 5 pens 28 Days Solostar • Just requires 1/3 less volume of insulin for the same number of units • Both pens dial up to a max of 80 units per injection ® ® • Lasts slightly longer than 24 hours • When switching from Toujeo to Lantus reduce dose by 20% • When switching from Lantus® to Toujeo® use the same number of units but monitor closely and begin titrating dose • Toujeo® requires higher doses than Lantus® for the same glycemic lowering effect

DEGLUDEC VS. GLARGINE (BEGIN-FLEX INSULIN DEGLUDEC (TRESIBA®) TRIAL)

•Long-acting basal insulin •Type 2 patients randomized •Duration up to 42 hours • Degludec once daily at same time each day •Injected once a day at • Degludec once daily at variable times each day • Glargine once daily at same time each day •U-100 and U-200 strengths

•Available only as a FlexTouch® Pen

DEGLUDEC VS. GLARGINE (BEGIN-FLEX TRIAL) INSULIN DEGLUDEC (TRESIBA®)

Pen Package Storage of in Max dose Dose Volume Size use pen per increment injection Tresiba® 3 mL 5 pens 56 Days 80 units 1 unit FlexTouch® (300 U-100 units) Tresiba® 3 mL 3 pens 56 Days 160 units 2 units FlexTouch® (600 U-200 units)

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NEW PRODUCTS THAT ARE PENDING COUNSELING CONSIDERATIONS

•Ryzodeg® 70/30 •New concentrations of Glargine U-300, Degludec U-200, and now • Insulin Degludec/ 70/30 (Humalog®) U-200 • FDA approved 9/2015 but not yet available • Caution patients not to use syringes to draw •Xultophy® insulin our of their pens • Fixed dose combination of Insulin Degludec •Different storage criteria of in use pen and liraglutide • Glargine U-300 42 days • Approved in Europe • Degludec U-100 and U-200 56 days • Has been awaiting Tresiba’s approval in the US •Degludec can dial up to 160 unit injection • Benefit for patients on larger insulin doses

NEW INHALED INSULIN • Afrezza: approved 6-27-14 • Human insulin inhalation powder • Rapid acting insulin • Boxed warning advising about acute GLP-1 Agonists bronchospasm risk in patients with asthma or COPD • Single use cartridges of 4, 8, and 12 units • Sanofi ended marketing agreement Jan 2016 • Unclear what the future of this product will be

GLP-1 Secretion and Inactivation GLP-1 PHYSIOLOGY

Mixed meal Intestinal GLP-1 GLP-1 secreted upon release the ingestion of food T1/2= 1 to 2 min

GLP-1 active

DPP-4

GLP-1 inactive (>80% of pool)

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® EXENATIDE (BYETTA®) LIRAGLUTIDE (VICTOZA )

•Dosing: • Dosing: 0.6 mg SQ once daily x 1 week • 5 mcg SC twice daily within 60 min of start of a • Then 1.2 mg SQ daily x 1 week meal • Can increase to 1.8 mg daily if needed • Increase to 10 mcg bid after 4 weeks • Timing of doses, independent of meals • Need to prescribe pen needles • Need to prescribe pen needles • Liraglutide is also FDA approved for obesity in a 3 mg once a day dose (Saxenda®)

EXENATIDE LONG ACTING (BYDUREON®) ALBIGLUTIDE (TANZEUM™)

•2 mg subq once a week •30 mg SQ once a week • Without regard to meals or time of day • Can increase to 50 mg once weekly • New Pen device just FDA approved 3-2014 • Without regard to meals or time of day • Now available in pharmacies • No renal adjustments

DULAGLUTIDE (TRULICITY™) GLP-1 AGONIST COMPARATIVE TRIALS

• 0.75 mg SQ once weekly •LEAD-6: Liraglutide vs. Exenatide BID x 26 • Can increase to 1.5 mg once weekly wks • Each pen is single use • A1C reduction: -1.12% vs. -0.79% (P<0.0001) • Patient does not see the needle when performing the •DURATION-1 AND DURATION-5: Exenatide injection LAR vs. Exenatide BID x 24 weeks • No mixing steps when performing the injection • A1C reduction: -1.6% vs. 0.9% (P<0.0001) • No renal adjustments •DURATION-6: Liraglutide vs. Exenatide LAR x 26 weeks • A1C reduction: -1.5% vs. -1.3% (P=0.02)

LEAD-6. Lancet. 2009;374(9683):39-47 DURATION-1. Diabetes Care. 2010;33(6):1255-61 DURATION-5. J Clin Endocrinol Metab. 2011;96(5):1301-10 DURATION-6. Lancet. 2013;381:117-24

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GLP-1 AGONIST ADVERSE GLP-1 AGONIST COMPARATIVE TRIALS EFFECTS/CONTRAINDICATIONS

• HARMONY 7: Albiglutide vs. liraglutide x 32 •Adverse Effects •Contraindications/Pr weeks non inferiority study • N/V, diarrhea ecautions • A1C reduction -0.78% vs. -0.99% p=0.0846 (did not meet non-inferiority criteria) • Weight loss (a good side • • Weight loss greater with liraglutide effect) • CrCl < 30 ml/min • -2.19 kg vs -0.64 kg p<0.0001 (exenatide) • Harmony 6: Albiglutide vs. Thrice daily Insulin • Gastroparesis Lispro in patients inadequately controlled with Insulin Glargine + oral agents • History of pancreatitis • A1C reduction -0.82 vs. -0.66 with insulin p<0.0001 • History of medullary • Met non-inferiority end point thyroid carcinoma • Weight -0.73 kg vs +0.81 kg with insulin • Multiple endocrine neoplasia syndrome HARMONY 7. Lancet Diabetes Endocrinol. 2014;2:289-297 2 Harmony 6. Diabetes Care 2014;2317-25

GLP-1 AGONIST CONSIDERATIONS • Low risk of • Weight loss • Albiglutide and dulaglutide have slightly less weight loss than the other agents DPP-IV Inhibitors • Potential for once daily or once weekly dosing • ADA treatment algorithm now includes GLP-1 agonists as a recommendation to add on to basal insulin • Variety of injection devices • Exenatide LAR and albiglutide pens require numerous steps • Dulaglutide least number of steps compared to the other once weekly injections • Exenatide and liraglutide pens resemble insulin pens and use the same needles

Inhibition of DPP-4 Increases Active GLP-1 AVAILABLE DPP-IV INHIBITORS ® Mixed Sitagliptin (Januvia ) meal • Intestinal GLP-1 •Saxagliptin (Onglyza™) release •Linagliptin (Tradjenta™) GLP--11 (7(7--36)36) activeactive •Alogliptin (Nesina™)

DPP-4

DPP-4 GLP-1 (9-36) inhibitor inactive

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DPP-IV INHIBITORS •Efficacy: A1C 0.5-0.7% •Similar efficacy for all four drugs SGLT2 Inhibitors •Less A1C reduction than with the GLP-1 agonists •Weight neutral •Adverse effects: very well tolerated •Low risk of hypoglycemia •Post-marketing reports of pancreatitis •One study showed increased CHF hospitalizations with saxagliptin, but not with the others

SGLT2 INHIBITORS – 1ST AGENT APPROVED 3/29/13 SGLT2 INHIBITORS • (Invokana™) •Sodium- • Dapagliflozin (Farxiga™) co- • Empagliflozin (Jardiance™) transporter • Once daily oral medications inhibitors • Low risk of hypoglycemia (SGLT2) • Weight loss •Increase • Adverse Effects: urinary • Female genital mycotic infections • UTI glucose • Increased urination excretion • 2015 FDA warning about ketoacidosis • Fracture risk?

SGLT2 INHIBITORS ADA Management of •EMPA-REG OUTCOME study • Cardiovascular safety study Hyperglycemia in Type 2 •7020 patients with established CVD randomized to empagliflozin or placebo Diabetes • Primary composite outcome: death from CV cause, nonfatal MI, or nonfatal stroke • 10.5% in empagliflozin group vs. 12.1% Standards of Medical Care in Diabetes 2015. Diabetes Care 2016;39(Suppl 1) placebo p=0.04 for superiority

• Death from CV causes: Management of Hyperglycemia in Type 2 Diabetes • 3.7% empagliflozin 5.9% in placebo 2015: A Patient Centered Approach. Diabetes Care 2015; 38:140-49 • 38% relative risk reduction

Zinman B, et al. NEJM 2015. published online September 17, 2015

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Approach to management of hyperglycemia: more less stringent stringent

Patient attitude and highly motivated, adherent, less motivated, non-adherent, expected treatment efforts excellent self-care capacities poor self-care capacities

Risks potentially associated low high with hypoglycemia, other adverse events

Disease duration newly diagnosed long-standing

Life expectancy long short

Important comorbidities absent few / mild severe

Established vascular absent few / mild severe complications

Resources, support system readily available limited

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

CONSIDERATIONS WHEN ADDING ON APPROACH TO STARTING AND ADJUSTING INSULIN IN TYPE 2 DIABETES 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 2nd line (or 1st line + metformin) when patient presents with significant hyperglycemia • Glucose >300 and/or A1C >10% or symptomatic • No evidence for using DPP-IV inhibitor with GLP-1 agonist • Consider insulin as 3rd agent especially when A1C is >9% and patient is already on 2 non-insulin drugs

2016 ADA GUIDELINES FOR GLYCEMIC, BP, & LIPID CONTROL 2016 ADA GUIDELINES HbA1C < 7.0% (individualization…..) Primary prevention: men and women ≥ age 50 with 1 additional risk factor Pre-prandial Aspirin glucose 80-130 mg/dL Secondary Prevention: all patients Postprandial with a history of CVD glucose < 180 mg/dL Tobacco Cessation Everyone who smokes Blood pressure < 140/90 mmHg

More closely matches ACC/AHA recommendations Lipids Age >40 receives statin regardless of LDL Does not require a risk calculation-simply presence of additional CV risk factor

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Questions

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