Wifi: Greenville ONE Center Updates for... · associated with diabetes medications • Review current trials that discuss renal outcomes in regards to diabetes medications • Evaluate

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Drug Updates in DiabetesAmy Robinson, PharmD, BCPSClinical Pharmacist – Ambulatory CareAnticoagulation Clinics and Center for Family MedicinePrisma Health – Upstate

Disclosure Statement

I have no conflicts of interest to disclose in regards to the information covered in this presentation.

Objectives

• Discuss cardiovascular outcome data associated with diabetes medications

• Review current trials that discuss renal outcomes in regards to diabetes medications

• Evaluate new insulin products and determine their place in therapy

• Recognize patient characteristics that would make patient good candidate for certain medications

Case 1LM is a 60 y/o male with Type II DM and HTN who comes to clinic for a hospital follow up after an NSTEMI; during his cardiac cath he was noted to have ischemic cardiomyopathy with EF 35%. Today he reports doing better overall; he feels short of breath walking short distances but is comfortable at rest.

Current Meds: Metformin 1000mg BID Lisinopril 5mg dailyPioglitazone 30mg daily Aspirin 81mg dailyCarvedilol 12.5mg BID Clopidogrel 75mg daily

ASCVD and DM

Type II DM

Increased Hospitalization for MI and Stroke2-4 fold increase in CVD

Decreased life expectancy by 6-7 years

ASCVD in DM Every 18mg/mL increase in FBG ~ 17% increase in future CVD

(Largest cause of morbidity and mortality)N Engl JMed 1998;339:229-34.J Am Coll Cardiol 2014;63:2935-59.Lancet 2014;383:2008-17.

HF in DM

Diabetes increases the risk of heart failure 2-5 fold

Heart failure mortality in the diabetic population is ~2x that of the non-diabetic population

Diabetes causes microvascular and macrovascular complications

Lancet 2015:385:2107-17.

FDA Mandate 2008

Must demonstrate an upper bound of the two-sided 95% CI of the risk ratio <1.8 preapproval for a composite end point of major adverse cardiac events (MACE)

• Nonfatal stroke• Nonfatal MI• CV death

All new Type II DM drug development programs should rule out unacceptable CV

risk.

Diabetes Care. 2016;39(5):738-742.U.S. Food and Drug Administration. Dec 2008.

Cardiovascular EffectsAgent ASCVD Effects Effects on HF

Metformin Benefit Neutral

Sulfonylureas* Neutral Neutral

TZDs Potential Benefit: Pioglitazone Increased risk

DPP-4 Inhibitors“-gliptans”

Neutral Potential risk: saxagliptin, alogliptin

SGLT-2 Inhibitors“-flozins”

Benefit: canagliflozin, empagliflozinNeutral: dapagliflozin

Benefit: canagliflozin, empagliflozin, dapagliflozin

GLP-1 agonists“-tides”

Benefit: liraglutide, dulaglutide, semaglutide, albiglutideNeutral: lixisenatide, exenatide XR

Neutral

Insulin Neutral Neutral

Riddle C, et al. Diabetes Care 2018; 41(1):S77*2nd generation

HF Risk with TZD’sStudy Drug Tested OutcomeRECORDHome et al. 2009

Rosaglitazone(Avandia)

Increased risk of fatal and non-fatalheart failure

PROactiveDormandy et al. 2005

Pioglitazone (Actos)

Decreased composite of all causemortality, non-fatal MI, and stroke, BUT increased risk of heart failure

DREAMGerstein et al. 2006

Rosaglitazone(Avandia)

Increase in non-fatal heart failure

Meta-analysis of 29 trialsHernandez et al. 2011

Rosaglitazone(Avandia) or pioglitazone (Actos)

TZD therapy is significantly and consistently associated with a higher risk of heart failure

Lancet. 2009;373(9681):2125–35.Lancet. 2005;366(9493):1279–89.Lancet. 2006;368(9541):1096–105.Am J Cardiovasc Drugs. 2011;11(2):115-28





DPP-4 Inhibitors“-gliptans”

Neutral Potential risk: saxagliptin, alogliptin

SGLT-2 Inhibitors“-flozins”

Benefit: canagliflozin, empagliflozinNeutral: dapagliflozin


GLP-1 agonists“-tides”

Benefit: liraglutide, dulaglutide, semaglutide, albiglutideNeutral: lixisenatide, exenatide XR

Neutral



DPP-4 InhibitorsSitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin

(Tradjenta), Alogliptin (Nesina)

CV Outcomes with DPP-4 Inhibitors

Trial Drug MACE* Hospitalizationsfor HF

All-cause mortality

SAVOR-TIMI 53

Saxagliptin(Onglyza)

___ ___

EXAMINE Alogliptin(Nesina)

___ ___ ___

TECOS** Sitagliptin(Januvia)

___ ___ ___

CAROLINA*** Linagliptin(Tradjenta)

___ ___ ___

*MACE= CV death, nonfatal stroke, nonfatal MI** MACE also included hospitalizations for unstable angina***Trial has not been published N Engl J Med. 2013;369:1317-26.

Lancet. 2015; 385: 2067-76.N Engl J Med. 2015; 373:232-42

DPP-4 Inhibitors and Heart Failure



DPP-4 Inhibitors vs. GLP-1 Agonists

Br J Cardiol. 2011;18:130–2.





DPP-4 Inhibitors Neutral Potential risk: saxagliptin, alogliptin

SGLT-2 Inhibitors Benefit: canagliflozin, empagliflozinNeutral: dapagliflozin


GLP-1 agonists Benefit: liraglutide, dulaglutide, semaglutide, albiglutideNeutral: lixisenatide, exenatide XR

Neutral

Insulin Neutral NeutralRiddle C, et al. Diabetes Care 2018; 41(1):S77*2nd generation

GLP-1 AgonistsExenatide (Byetta; ER- Bydureon), Liraglutide (Victoza), Lixisenatide (Adlyxin), Abiglutide (Tanzeum), Dulaglutide

(Trulicity), Semaglutide (Ozempic)

GLP-1 Receptor AgonistsTrial Drug MACE* Hospitalizations

for HFAll-cause Mortality

ELIXA** Lixisenatide(Adlyxin)

___ ___ ___

LEADER Liraglutide(Victoza)

___

SUSTAIN-6 Semaglutide(Ozempic)

___ ___

EXSCEL Exenatide XR(Bydureon)

___ ___

HARMONY Albiglutide(Tanzeum)

___ ___

REWIND Dulaglutide(Trulicity)

___ ___

Cefalu WT, et al. Diabetes Care 2018; 41:14-31 *MACE= CV death, nonfatal stroke, nonfatal MI**MACE also included hospitalizations for unstable angina

FDA-New Indications

• Liraglutide (Victoza)• Reduce the risk for myocardial infarction,

stroke, and cardiovascular death in adults with Type II DM who have established cardiovascular disease

Diabetes Care. 2019;42:S1-S193.






SGLT-2 Inhibitors Benefit: canagliflozin, empagliflozinNeutral: dapagliflozin



Neutral



SGLT-2 Inhibitors

Clin J AM Soc Nephrol. 2017;12(4):700-710

Cangliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance)

SGLT-2 Inhibitors

Trial Drug MACE* Hospitalizationsfor HF

All-causeMortality

EMPA-REG Empagliflozin(Jardiance)

CANVAS Canagliflozin(Invokana)

___

DECLARE-TIMI** Dapagliflozin(Farxiga)

___ ___

*MACE= CV death, nonfatal stroke, nonfatal MI**MACE also included composite CV death or hospitalization for HF

N Engl J Med. 2015; 373(22):2117-28.N. Engl J Med. 2017; 377(7):644-57.N Engl J Med. 2019;380 (4):347-57.

FDA- New Indications

• Empagliflozin (Jardiance)• Improve survival in adults with Type II DM

and cardiovascular disease• Canagliflozin (Invokana)

• Risk reduction of major cardiovascular events in adults with Type II DM and established cardiovascular disease




Renal Outcomes: SGLT-2 Inhibitors

Trial Drug CompositeRenal Outcome*

Other significant renal outcome

EMPA-REG Empagliflozin(Jardiance)

Decreased progression to macroalbuminuria

CANVAS Canagliflozin(Invokana)

Decreased new onset microalbuminuria and decreased macroalbuminuria

DECLARE-TIMI**

Dapagliflozin(Farxiga)

*Composite Renal Outcome= doubling of SCr, initiation of renal replacement therapy, death from renal disease** Included ≥40% decrease in eGFR to <60mL/min

Nephrol Dial Transplant. (2019) 34:208-230.

CREDENCE Trial

Characteristics Canagliflozin N=2202

PlaceboN=2199

Hazard Ratio(95% CI) P Value

Primary Outcome

Primary Composite 245 340 0.70 (0.59-0.82) 0.00001

SCr doubling 118 188 0.60 (0.48-0.76) <0.001

ESRD 116 165 0.68 (0.54-0.86) 0.002

Renal death 2 5 NA NA

CV death 110 140 0.78 (0.61-1.00) 0.05

Secondary Outcomes

CV death or hospitalization for HF 179 253 0.69 (0.57-0.83) <0.001

3P-MACE 217 269 0.80 (0.67-0.95) 0.01

Hospitalization for HF 89 141 0.61 (0.47-0.80) <0.001

ESRD, doubling of SCr, or renal death 153 224 0.66 (0.53-0.81) <0.001

FDA- New Indication?

• Canagliflozin• Manufacturer submitted supplemental New

Drug Application to FDA seeking new indication to reduce risk of ESRD, doubling of SCr, and renal or CV death in patients with Type II DM (March 2019)

• May 2019- FDA granted priority review

Afferent arteriole constriction

Diabetologia (2018) 61:2108-17.

Renal Outcomes: GLP-1 Agonists

• Several cardiovascular outcome trials displayed reduced composite renal outcomes with GLP-1 agonists

• LEADER (liraglutide)• SUSTAIN-6 (semaglutide)• EXSCEL (exenatide ER)• REWIND (dulaglutide)

• Composite outcome mainly driven by new onset macroalbuminuria in these trials

Diabetes Care 2019;42:S90-102

Current Guidelines1. Evaluate if patient is on

first line therapy and implementing lifestyle modifications

2. Establish predominating disease state

3. Initiate initial therapy

4. Intensify as needed to provide maximum benefits

Case 2

JM is a 68 y/o male with Type II DM (A1c 9.7), HTN, HFrEF (EF 40%), and CKD (eGFR35mL/min). His current BMI is 44 and he is interested in losing weight.

Current Meds: Metformin 1000mg daily Losartan 100mg dailyGlipizide 10mg daily Aspirin 81mg dailyCarvedilol 25mg BID Furosemide 40mg dailyAtorvastatin 40mg daily






SGL-T2 Inhibitors Benefit: canagliflozin, empagliflozinNeutral: dapagliflozin



Neutral


Riddle C, et al. Diabetes Care 2018; 41(1):S77

*2nd generation

SGLT-2 InhibitorsCanagliflozin (Invokana)

Dapagliflozin (Farxiga)

Ertugliflozin(Steglatro)

Empagliflozin (Jardiance)

Initial dose (max dose)

100 mg/d if eGFR is 45-59

100 - 300 mg/d if eGFR > 60

5 mg/d (10 mg/d)

5 mg/d (15 mg/d)

10 mg/d (25 mg/d)

Renal doseadjustments

Do not initiate ifeGFR is < 45*CI: eGFR < 30

DC if eGFR < 45CI: eGFR < 30

Do not initiate/ DC if eGFR < 60CI: eGFR < 30

Do not initiate / DC if eGFR < 45CI: eGFR < 30

Administration Take prior to first meal Take in the morning without regard to meal

eGFR: estimated glomerular filtration rate (mL/min/1.73m²) | DC: discontinue | CI: contraindicated*Does not take CREDENCE trial into account

Jardiance (empagliflozin) [prescribing information]. Boehringer Ingelheim Pharmaceuticals, Inc; October 2018.Farxiga (dapagliflozin) [prescribing information]. AstraZeneca Pharmaceuticals LP; February 2019.

Invokana (canagliflozin) [prescribing information]. Janssen Pharmaceuticals; October 2018.Steglatro (ertugliflozin) [prescribing information]. Merck Sharp & Dohm Corp; October 2018.

FDA Warnings

2015• Bone fracture risk / reduced bone mineral density• Warnings about lactic acidosis and serious UTIs

2016

• Possible increased risk of leg & foot amputations with canagliflozin

• Acute kidney injury warnings strengthened

2017• Increased risk of amputations confirmed with

canagliflozin

2018• Rare occurrences of Fournier’s gangrene with SGLT-2

inhibitors, class-wide

U.S. Food and Drug Administration. 2019.

GLP-1 AgonistsInitial Dose (max dose)

Frequency Renal Dose Adjustments

Lixisenatide(Adlyxin)

10mcg (20mcg)

Daily (increase dose to 20mcg on Day 15)

Do not use eGFR <15 mL/min

Liraglutide(Victoza)

0.6mg(1.8mg)

Daily (increase dose by 0.6mg weekly)

Semaglutide(Ozempic)

0.25mg (1mg)

Weekly (increase dose by 0.25mg every 4 weeks)

Exenatide (IR Byetta; ER Bydureon)

5mcg (IR)2mg (ER)

IR: twice daily (can increase to 10mcg BID after 1 monthER: weekly

IR: Do not use CrCl <30 mL/minER: Do not use eGFR <45 mL/min

Albiglutide(Tanzeum)

30mg (50mg)

Weekly

Dulaglutide(Trulicity)

0.75mg (1.5mg)

Weekly


Advantages Disadvantages

• Weight loss• Option of once weekly

injection• Cardiac benefit• Efficacy

• Risk of thyroid C-cell tumors• Gastrointestinal side effects

(nausea, vomiting, diarrhea, delayed gastric emptying)

• Injection• Possible risk of pancreatitis

GLP-1 Agonists


Case 2JM is a 68 y/o male with Type II DM (A1c 9.7), HTN, HFrEF (EF 40%), and CKD (eGFR 35mL/min). His current BMI is 44 and he is interested in losing weight.

Current Meds: Metformin 1000mg daily Losartan 100mg dailyGlipizide 10mg daily Aspirin 81mg dailyCarvedilol 25mg BID Furosemide 40mg dailyAtorvastatin 40mg daily

New Injectables• New insulins• Fixed Dose combinations

Toujeo® (Insulin Glargine U-300)• Unit-to-Unit (no dose recalculation)• 2 pens available

• Longer acting up to 36 hours?• Less weight gain, less severe nocturnal hypoglycemia*• Patients needed 10-20% more to achieve similar

glycemic control

Pen Size Units per Pen Injection Limit

Toujeo® 1.5 mL 450 units 80 unitsToujeo Max® 3 mL 900 units 160 units (2 unit

increments)

*Compared to LantusToujeo® [Package Insert]. 2015.Diabetes Care. 2015;37(10):2755-62.

Tresiba® (Insulin Degludec)

• 2 concentrations (U-100 and U-200)

• Full 24 hours of blood glucose control; lasts 42 hours

• Adjustable daily dose timing• Less variability, less symptomatic hypoglycemia,

less nocturnal symptomatic hypoglycemia*

Pen Size Units per Pen Injection LimitU-100 3 mL 300 units 80 unitsU-200 3 mL 600 units 160 units (2 unit

increments)

*Compared to Lantus Tresiba [Package Insert]. 2015.JAMA. 2017;318(1):45-56.

Ultra-Long Acting Insulin

American Diabetes Association;2015: 1-68.

Fiasp® (Insulin Aspart)

Drug Onset Peak DurationFiasp® 2.5 minutes 30 minutes – 1

hour5-7 hours

Novolog® <15 minutes 30 minutes – 1 hour

3-5 hours

• Lower 1 hour post-prandial plasma glucose levels compared to Novolog®

• More hypoglycemic events and had the same post-prandial glucose levels as Novolog® 3 and 4 hours postmeal

Diabetes Care. 2017.

Biosimilars

Admelog (Insulin lispro) Basaglar (Insulin glargine)Trial SORELLA 2 ELEMENT 2Design Randomized, open-label Randomized, double blindPatients Previously treated with

multiple injections while using insulin glargine

Insulin-naïve or previously treated with insulin glargline

Results Change in A1c from baseline: -0.92% vs. -0.85%

Change in A1c from baseline -1.29% vs. -1.34%

**Not interchangeable

Diabetes Obes Metab. 2015;17(8):734-41.Diabetes Technol Ther. 2018;20(1):49-58.

Case 3

BR is a 58 y/o male with Type II DM who comes to you as a new patient. Currently, he is not taking any medications for diabetes, but was previously prescribed metformin 1000mg BID and glipizide ER 20mg daily. His A1c today is 11.6%.

Current Guidelines


Fixed Ratio Combination Injectables

Soliqua® Xultophy®Components Insulin glargine &

lixisenatideInsulin degludec & liraglutide

Strength 1 unit/0.33mcg 1 unit/0.036mgDosing (based on current insulin dose)

<30 units or on lixisenatide= 15 units30-60 units = 30 units

<50 units or ≤1.8 liraglutide= 16 units

Titration 2-4 units weekly 2 units every 3-4 days

Max Dose 60 units insulin 50 units insulinContraindications CrCl <15mL/min

Soliqua. [Package Insert]. 2016.Xultophy. [Package Insert]. 2016.

Fixed Ratio Combination InjectablesLimitations Advantages• Starting dose• Titration of insulin• Max dose of insulin

• Similar glycemic outcomes• 1 additional injection vs.

multiple injections• Weight loss• Less hypoglycemia

Case 3

BR is a 58 y/o male with Type II DM who comes to you as a new patient. Currently, he is not taking any medications for diabetes, but was previously prescribed metformin 1000mg BID and glipizide ER 20mg daily. His A1c today is 11.6%.

Summary• Current ADA guidelines have been updated to

reflect current cardiovascular and renal outcomes for diabetic medications

• Expect guidelines to continuously be updated as more trials are published

• GLP-1 agonists are now first-line agents for injection therapy

• Fixed Ratio Combination Injectables provide a one injection option for some patients

• Biosimilars and new insulin products continue to come to market

Drug Updates in DiabetesAmy Robinson, PharmD, [email protected] Pharmacist – Ambulatory CareAnticoagulation Clinics and Center for Family MedicinePrisma Health – Upstate

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Wifi: Greenville ONE Center Updates for... · associated with diabetes medications • Review current trials that discuss renal outcomes in regards to diabetes medications • Evaluate