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Type 2 Diabetes: Latest Drug Approvals and Use

of the Newer Agents

Gretchen Ray, PharmD, PhC, BCACP, CDEAssociate Professor, UNM College of

PharmacyOctober 9th, 2017

gray@salud.unm.edu

OBJECTIVES

•Describe the recently approved insulins

•Compare and contrast the GLP-1 receptor agonists and the recent literature supporting this drug class

•Describe the available SGLT2 inhibitors and the efficacy and safety profile of this drug class

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UPDATED GUIDELINES

•Standards of Medical Care in Diabetes 2017. Diabetes Care 2017;40(Suppl 1)

DIABETES MEDICATIONS

1960 1995 2000 2005 2010 2015

Insulin1922SUs1957

MetforminAGIs1995

GlinidesTZDs1997

ExenatidePramlintide

2005

Sitagliptin2006

Liraglutide2010

Saxagliptin2009

Linagliptin2011

2012ExenatideLAR

CanagliflozinAlogliptin

2013DapagliflozinEmpagliflozin

AlbiglutideDulaglutide

Afrezza inhaledinsulin

2014

U-300 GlargineInsulin Degludec

Basaglar2015

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• Rapid Acting• Humalog® (lispro) (U-100 and U-200)• Novolog ® (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)

TYPES OF INSULIN

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

• Higher concentration of Insulin Glargine

• Only available in pen form

• Lasts slightly longer than 24 hours

• Converting from U-100 Glargine to U-300 Glargine

• 1:1 then titrate up• Typically a higher dose of Toujeo® is required

• Converting from U-300 Glargine to U-100 Glargine

• Use 80% of the dose of Toujeo®

Toujeo. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 12, 2017

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EDITION CLINICAL TRIAL SERIES. GLARGINE U-300 VS. U-100 HYPOGLYCEMIA RISK

EDITION 1

• U-300 led to 21% relative risk reduction of ≥ 1 hypoglycemic event from week 9 to month 6 (p=0.0045)1

EDITION 2

• U-300 led to 23% relative risk reduction of ≥ 1 hypoglycemic event from week 9 to month 6 (p=0.038)2

EDITION 3

• Similar rate of hypoglycemia from week 9 to month 6 in both groups (p=0.45)3

1Diabetes Care. 2014;37(10):2755-27622Diabetes Care. 2014;37(12):3235-32433Diabetes Obes Metab. 2015;17

META-ANALYSIS OF EDITION 1, 2, AND 3

•Slightly less weight gain with U-300 vs. U-100

• LS mean difference -0.28, 95% CI -0.55 to -0.01

•Higher mean basal insulin dose at month 6 in the U-300 group

• 0.85 units/kg/day U-300 vs. 0.76 units/kg/day U-100

•Comparable A1C reduction in both groups

Ritzel R, et al. Diabetes Obesity and Metabolism. 2015

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INSULIN DEGLUDEC (TRESIBA®)

•Ultra-Long-acting basal insulin

•Duration up to 42 hours

• Injected once a day at any time of day

•U-100 and U-200 strengths

•Available only as a FlexTouch® Pen

Tresiba. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 12, 2017

DEVOTE: EFFICACY AND SAFETY OF DEGLUDECVS. GLARGINE IN TYPE 2 DIABETES

•Primary Outcome: first occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke

•Secondary: number of severe hypoglycemic episodes, time from randomization to MACE + time to hospitalization for unstable angina pectoris, number of serious adverse events, AEs leading to discontinuation of treatment drug.

Marso SP, et al. NEJM. 2017;377(8):723-32

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DEVOTE: EFFICACY AND SAFETY OF DEGLUDECVS. GLARGINE IN TYPE 2 DIABETES

• Duration of follow-up: 1.99 years

• Mean patient age: 65 years

• Diabetes duration: 16.4 years

•Key inclusion criteria: • adult patients with type 2 diabetes, age ≥ 50

years with predefined previous CVD or renal disease

• OR age ≥ 60 years with at least one predefined CV risk factor

• A1C ≥ 7.0% or A1C < 7.0% and current insulin treatment corresponding to ≥ 20 units basal insulin per day; and patients on one or more oral or injectable antidiabetic agent(s).

Marso SP, et al. NEJM. 2017;377(8):723-32

DEVOTE: EFFICACY AND SAFETY OF DEGLUDECVS. GLARGINE IN TYPE 2 DIABETES

Outcome Degludec(no./100 pt

years)

Glargine (no./100 pt

year)

Ratio (95% CI), P-value

NNT

Primary Composite

4.29 4.71 HR 0.91(0.78-1.06) P<0.001 for non-inferiority

Severe Hypoglycemia

3.7 6.25 RR 0.60(0.48-0.76)p<0.001 for superiority

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Marso SP, et al. NEJM. 2017;377(8):723-32

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LONG ACTING INSULIN PREPARATIONSPen/vial Volume

Pen Package Size

Storage of in use pen or vial at room temp

Max Dose Pen can Dial/injection

Pen Dose increment

Tresiba®

FlexTouch®

U-100

3 mL (300 units)

5 pens 56 Days 80 units 1 unit

Tresiba®

FlexTouch®

U-200

3 mL (600 units)

3 pens 56 Days 160 units 2 units

Toujeo® U-300

1.5 mL (450 units)

3 or 5 pens

42 Days 80 units 1 unit

Lantus® 3 mL (300 units) or 1 vial (1000 units)

5 pens 28 Days 80 units 1 unit

Basaglar® KwikPens

3mL (300 units)

5 Pens 28 days 80 units 1 unit

Levemir® 3 mL (300 units) or 1 vial (1000 units)

5 pens 42 Days 80 units 1 unit

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 our of their pens

•Different storage criteria of in use pen for each product

•Maximum dose each pen can dial up to

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GLP-1 Receptor Agonists

GLP-1 Secretion and Inactivation

IntestinalGLP-1release

GLP-1 active

Mixed meal

GLP-1 inactive(>80% of pool)

DPP-4

T1/2= 1 to 2 min

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GLP-1 PHYSIOLOGY

GLP-1 secreted upon the ingestion of food

EXENATIDE (BYETTA®)

•Dosing:• 5 mcg SC twice daily within 60 min of start of a meal

• Increase to 10 mcg bid after 4 weeks• Need to prescribe pen needles

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LIRAGLUTIDE (VICTOZA®)

• Dosing: 0.6 mg SQ once daily x 1 week

• Then 1.2 mg SQ daily x 1 week

• Can increase to 1.8 mg daily if needed

• Timing of doses, independent of meals

• 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®)

•2 mg subq once a week

• Without regard to meals or time of day

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ALBIGLUTIDE (TANZEUM™)

•Will no longer be on the market as of 2018

DULAGLUTIDE (TRULICITY™)

• 0.75 mg SQ once weekly

• Can increase to 1.5 mg once weekly

• Each pen is single use

• Patient does not see the needle when performing the injection

• No mixing steps when performing the injection

• No renal adjustments

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FUTURE GLP-1 AGONISTS

•Semaglutide: once weekly injectable and daily oral formulation in trials

GLP-1 AGONIST ADVERSE EFFECTS/PRECAUTIONS

•Adverse Effects

• Nausea and vomiting –most common AE

• Anti-exenatide antibodies• Very rare

• Cases of acute pancreatitis

•Contraindications/Precautions

• Type 1 diabetes

• Gastroparesis

• History of pancreatitis

• History of medullary thyroid carcinoma

• Multiple endocrine neoplasia syndrome 2

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GLP-1 AGONIST BENEFITS

•Low risk of hypoglycemia

• 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 2017. Diabetes Care2017;40(Suppl 1)

GLP-1 RA CV Safety Trials

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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 occurance 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 noninferiority; p=0.01 for superiority)

N Engl J Med 2016;375:311-22

• Injectable once a week semaglutide(GLP-1 agonist) was superior to placebo in improving glycemic control and ↓ CV events in high-risk patients with diabetesPlacebo

(n = 1,649)Semaglutide(n = 1,648)

SUSTAIN-6: SEMAGLUTIDE CV SAFETY TRIAL

• Primary outcome, CV death/MI/stroke: semaglutidevs. 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%

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

Conclusions

Marso SP, et al. N Engl J Med 2016;375:1834-44

Primary outcome

%

pnoninferiority < 0.001 psuperiority = 0.02

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GLP-1 RA CV STUDIES DEMONSTRATING NON-INFERIORITY

•ELIXA1-lixisenatide

•EXSCEL2- exenatide LAR

1. Pfeffer MA, et al. NEJM. 2015;373(23):2247-572. Holman RR, et al. NEJM. 2017 Sept 14; epub ahead of print

GLP-1 Agonist/Basal Insulin Combination Pens

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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

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SGLT2 Inhibitors

SGLT2 INHIBITORS

•Sodium-glucose co-transporter inhibitors (SGLT2)

• Increase urinary glucose excretion

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SGLT2 INHIBITORS

•Canagliflozin (Invokana™)

•Dapagliflozin (Farxiga™)

•Empagliflozin (Jardiance™)

• Once daily oral medications

•Low risk of hypoglycemia

•Weight loss

SGLT2 INHIBITORS

Side Effects/Precautions

• Female genital mycoticinfections

• 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

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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

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EMPA-REG: PRIMARY OUTCOME:3-POINT MACE

HR 0.86(95.02% CI 0.74, 0.99)

p=0.0382

Zinman B, et al. NEJM 2015. 373 (22):2117-28

Patients with event/analyzedEmpagliflozin 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

0.25 0.50 1.00 2.00

EMPA-REG:CV DEATH, MI AND STROKE

Favors empagliflozin Favors placebo

Zinman B, et al. NEJM 2015. 373 (22):2117-28

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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

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CANVAS AND CANVAS-R

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

Renal outcomes

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

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ADA Management of Hyperglycemia in Type 2

Diabetes

Standards of Medical Care in Diabetes. Diabetes Care 2017;40(Suppl 1)

How to Progress After Triple Therapy

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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 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

• In patients with long-standing diabetes and established ASCVD, empagliflozin or liraglutideshould be considered as they have been shown to reduce CV and all-cause mortality

Standards of Medical Care in Diabetes. Diabetes Care 2017;40(Suppl 1)

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Questions