powerpoint presentation€¦ · 2016;133(24):2459-2502. figure: diabetes spectrum....

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GETTING TO THE HEART OF TYPE 2 DIABETES MANAGEMENT: AN UPDATE ON CARDIOVASCULAR

OUTCOME TRIAL RESEARCH

KATHRYN LITTEN, PHARMDPGY2 AMBULATORY CARE RESIDENTCOMMUNITYCARE HEALTH CENTERSUNIVERSITY OF TEXAS AT AUSTIN COLLEGE OF PHARMACY

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PHARMACIST OBJECTIVES

Discuss the increased risk of cardiovascular disease in patients with type 2 diabetes

Review results of landmark and recent cardiovascular outcome trials

Analyze the effect of combination therapy with a sodium glucose cotransporter 2 inhibitor and a glucagon-like peptide-1 receptor agonist on cardiovascular-related outcomes

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TECHNICIAN OBJECTIVES

Discuss the increased risk of cardiovascular disease in patients with type 2 diabetes

Review medication used to treat type 2 diabetes and name side effects of each

Analyze the effect of SGLT2 inhibitors and GLP-1 receptor agonists on weight and blood pressure

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ASSESSMENT QUESTION

What is the only GLP1-RA with an FDA indication for reduction of CV events in patients with ASCVD and T2DM

A. Bydureon (exenatide)

B. Victoza (liraglutide)

C. Trulicity (dulaglutide)

D. Byetta (exenatide)

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ASSESSMENT QUESTION

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What are the only SGLT2 inhibitors with FDA indications for reduction of CV events or CV mortality in patients with T2DM

A. Jardiance (empagliflozin)

B. Invokana (canagliflozin)

C. Farxiga (dapagliflozin)

D. A + B

E. B + C

POLL

What is your favorite second line antidiabetic class after metformin for a Type 2diabetic patient without complications?

A. Sulfonylurea

B. DPP4 Inhibitor

C. GLP-1 RA

D. SGLT2 inhibitor

E. Other

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CARDIOVASCULAR DISEASE AND DIABETES

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD)

Atherosclerotic cardiovascular disease (ASCVD) occurs 14.6 years earlier and is more severe in patients with Type 2 diabetes

Diabetes Care. 2018;41(Suppl. 1):S86–S104.Photo: https://diabetesheartconnection.org/

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Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes

40% ischemic heart disease15% other heart disease10% strokes

Increased mortality risk in: • Young patients• Poor glycemic control• Renal complications

Circulation. 2016;133(24):2459-2502. Photo: https://wustl.edu/about/university-facts/

2/3 deaths due to ASCVD 8


Cardiovascular disease is the leading cause of direct and indirect costs in patients with diabetes

Diabetes Care. 2018;41(Suppl. 1):S86–S104.

2,108per patient each year

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The American Heart Association major risk factors for CVD:

• Smoking• Hypertension• Hyperlipidemia• Diabetes• Obesity

• Age• Gender• Family History• Physical

inactivityCirculation. 2016;133(24):2459-2502. Figure: Diabetes Spectrum. 2003;16(2):120-125.

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AMERICAN DIABETES ASSOCIATION GUIDELINES

Aspirin Therapy

• ASA 81 mg daily if

>50 years old with

>1 risk factor & not

at increased risk of

bleeding

• 2◦ MI or stroke

prevention

Weight

•Weight loss

through caloric

restriction and

physical activity

Lipids

•High intensity

statin- ASCVD, 10-

yr risk >20%, or

multiple RFs

•Moderate

intensity statin -

ages >40 yo with

LDL >70

Blood Pressure

•<140/90 mmHg

for ASCVD <15%

•<130/80 mmHg if

ASCVD >15%

HbA1c

•ADA: <7%

•AACE: <6.5%

Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes – 2019Assess CV risk factors at least annually

Diabetes Care. 2019;41(Suppl. 1):S86-S104 11

Endorsed by the American College of Cardiology

for the 1st time! STEP IN THE RIGHT DIRECTION

2008 FDA Guidance for Industry – Diabetes Mellitus

Requires phase 2 and 3 trials for new antidiabetic therapies to evaluate cardiovascular risk, including:

Cardiovascular mortality

Myocardial infarction and stroke

Hospitalization for acute coronary revascularization procedures

Other endpoints

Diabetes Care. 2018;41(Suppl. 1):S86–S104.

Must prove it will not increase CV risk “to an unacceptable event”

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CARDIOVASCULAR OUTCOME TRIALS

ACE

2013 2015 2016 2017 2018 2019 2020

EXAMINE

SAVOR-TIMI

TECOS

EMPA-REG OUTCOME

SUSTAIN-6

LEADER

ELIXA

IRIS

FREEDOM-CVD

DEVOTE

EXSCEL

CARMELINA

PIONEER 6

REWIND

HARMONY

CAROLINA

VERTIS CV

DAPA-HF

DECLARE-TIMI 58

CREDENCE

DAPA-CKD

EMPEROR-Preserved

EMPEROR-Reduced

ALPHA GLUCOSIDASE INHIBITOR

INSULINTZD

GLP-1 RASSGLT2IDPP4-I

KEY

CANVAS

AACE Type 2 Diabetes Management Algorithm 2018

MetGLP-1

RASGLT2-i DPP4 AGi TZD SU Insulin PRMAL

Hypoglycemia

Weight

Renal

GI SEs

Cardiac

PROFILES OF ANTIDIABETICS

Positive Neutral Moderate Severe

AMERICAN DIABETES ASSOCIATION GUIDELINES

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Type 2 Diabetes

ASCVDSGLT2i or GLP1RAs

Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes – 2019Assess CV risk factors at least annually

Type 2 Diabetes

ASCVD

Heart failure or

risk of heart failure

SGLT2i

Diabetes Care. 2019;41(Suppl. 1):S86-S104

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AACE.

2017

DPP4 INHIBITORS

SAVOR-TIMI 53 EXAMINE TECOS

Drug vs. Placebo Saxagliptin Alogliptin Sitagliptin

Inclusion criteria History or RFs for CVD ACS within 15-90 days Preexisting CVD

Prior CVD % 78 91 80

A1c change -0.3% -0.3% -0.3%

Primary Outcome-MACE

1.00 (0.89-1.12) 0.96 (0.95-1.16) 0.98 (0.89-1.08)

CV Death 1.03 (0.87-1.22) 0.85 (0.66-1.10) 1.03 (0.89-1.19)

HF hospitalization 1.27 (1.07-1.51) 1.19 (0.90-1.58) 1.00 (0.83-1.20)

All cause mortality 1.11 (0.96-1.27) 0.88 (0.71-1.09) 1.01 (0.90-1.14)

17MACE: Major adverse cardiovascular events; HF: Heart failure

N Engl J Med. 2013;369:1317-1326.Am Heart J. 2011162(4):620-626.JAMA Cardiol. 2016;1(2):126-135.

GLUCAGON LIKE PEPTIDE-1 RECEPTOR AGONISTS

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GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

Meier JJ. Nat Rev Endocrinol.2012;8:728-742.19


Table 2: Comparison of GLP-1 RAs

Drugs Dose A1c Lowering Cost (Monthly)

Dulaglutide

(Trulicity)Weekly ~1.5% $675

Exenatide

(Byetta)Twice daily ~1% $710

Exenatide

(Bydureon)Weekly ~1.5% $660

Liraglutide

(Victoza) Daily ~1.5%

Daily:

1.2 mg: $540

1.8 mg: $805

Lixisenatide

(Adlyxin)Daily ~1% $590

Semaglutide

(Ozempic)Weekly ~1.5% $675

Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. January 2017.Clinical Resource, Drugs for Type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter. January 2017.

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Albiglutide (Tanzeum) discontinued 8/2017


Reduce post prandial blood glucose

Low risk for hypoglycemia

Side effects

Nausea

Injection site reactions

Monitoring

ADEs

Hypoglycemia

Weight

BP

Renal function

Dose reductions for albiglutide, dulaglutide

Warnings

Pancreatitis (rare)

Exenatide, liraglutide

Gallbladder disease

Semaglutide

Retinopathy complications

Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. January 2017.Clinical Resource, Drugs for Type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter. January 2017.

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LEADER TRIAL

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

Purpose: To determine if liraglutide reduces CV risk in patients with T2DM and high risk for CV events

Placebo run-in

Liraglutide 0.6 – 1.8 mg

Placebo

Safety follow-up

Safety follow-up

Double-blinded410 sites in 32 countries

Randomization 1:1Screening End treatment

+ standard of care

2 weeks 3.5-5 years 30 days

N Engl J Med. 2016; 375:311–322.23

LEADER TRIAL

Participants

T2DM at high risk for cardiovascular disease

Mean age 64 yo, duration of diabetes ~13 years, HbA1c 8.7%

~80% of patients >50 yo had established CVD*, ~20% of patients >60 yo were at high risk

~76% of patient on metformin, 44% on insulin

CV medications: statins and antihypertensives - similar among groups

More patients in the liraglutide group were on

Antiplatelets (68.7% vs 66.8%, p=0.05)

Beta blockers (56.8% vs 54.1%, p=0.009)

N Engl J Med. 2016; 375:311–322.

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LEADER TRIAL

OutcomeLiraglutide

n= 4668Placebo n= 4672

P value NNT

Primary compositeoutcome

13.0% 14.9%0.01 superiority,

<0.001 non-inferiority66

Death from CV causes

4.7% 6.0% 0.007 77

Death from any cause

8.2% 9.6% 0.02 71

No difference in non-fatal MI, stroke, or heart failure hospitalization

HbA1c 0.40% Weight 2.3 kg SBP 1.2 mmHgLiraglutide:

N Engl J Med. 2016; 375:311–322.25

LEADER TRIAL

Liraglutide reduces CV events in patients with T2DM at high risk for CVD

Conclusion

N Engl J Med. 2016; 375:311–322.26

HARMONY OUTCOMES TRIAL

Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease: A double blind randomized placebo-controlled trial

Purpose: To determine if albiglutide reduces CV risk in patients with T2DM

Placebo run-in

Albiglutide 30-50 mg

Placebo


Randomization 1:1Screening End treatment2 weeks 1.6 years 30 days

Lancet. 2018; 392:1519–29.

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Participants

T2DM with established cardiovascular, cerebrovascular, or peripheral arterial circulation disease

Mean age 64 yo, duration of diabetes ~14.2 years, HbA1c 8.7%

Coronary artery disease: 71%; stroke: 18%



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Lancet. 2018; 392:1519–29.


OutcomeAlbiglutide


P value


7% 9%0.0006 superiority,

<0.001 non-inferiority

MI 4% 5% 0.003

Stroke 2% 2% 0.30

Death from CV causes 3% 3% 0.58

Death from any cause 4% 4% 0.64

No difference in adverse effects

HbA1c 0.63% Weight 0.66 kg SBP 0.65 mmHgAlbiglutide:

29

Lancet. 2018; 392:1519–29.


Albiglutide reduces CV events in patients with T2DM with ASCVD

Conclusion

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Lancet. 2018; 392:1519–29.

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REWIND TRIAL

Researching Cardiovascular Events with a Weekly Incretin in Diabetes

Dulaglutide 1.5 mg weekly vs. placebo

Not yet published - Eli Lilly Press Release – 11/5/2018

9,901 participants - Baseline A1c 7.3%, ASCVD 31%

Follow up: 5 years

Outcome: Dulaglutide reduced MACE

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https://investor.lilly.com/news-releases/news-release-details/trulicityr-dulaglutide-demonstrates-superiority-reduction

MECHANISM FOR CV BENEFIT

Photo: The Heart FoundationDiabetes Ther. 2018;9:919-926. Diabetes Obes Metab. 2017;19:1353-1362.

GLP-1 RA

Activate cardiomyocytes

↑ Myocardial contraction

Vasodilate

↓ Ischemia-induced

myocardial damage

↓ Size and promote stability of atheromatous

plaques32

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Vitals

Height 5’6

Weight 220 lbs

Blood Pressure 145/95 mmHg

Patient Case

Patient JK – 56 yo F

CC: “My sugars are still high”

PMH: T2DM x 7y, HTN, HFpEF, osteoporosis

A1c 9.0%

ASCVD 10y risk: 11%

Medications

Metformin 1g BID

Levemir 20 units nightly

Lisinopril 10 mg daily

Vit D/Calcium supplement

FBG 7 day avg: 195

3 lows last week after lunch while at work

What medication class would be best to start in this patient?

A. Sulfonylurea

B. Thiazolidinedione (TZD)

C. GLP-1 RA

D. DPP4i

E. SGLT2i

SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS(SGLT2I)

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SGLT2 INHIBITORS

Wright EM, et al. Physiol Rev. 2011;91:733-79435

SGLT2 INHIBITORS

Table 4: Comparison of SGLT2s7

Drugs Dose Cost

Canagliflozin

(Invokana)

100-300 mg PO

daily $465

Dapagliflozin

(Farxiga)

5-10 mg

PO daily $465

Empagliflozin

(Jardiance)

10-25 mg

PO daily $465

Ertugliflozin

(Steglatro)

5-15 mg

PO daily $270

Lower HbA1c: 0.7-1%

Low risk for hypoglycemia

Side effects

Genital fungal/yeast infections

UTIs

Ketoacidosis

Dizziness

Hypotension

↑ LDL

↑ Urination

Clinical Resource, Drugs for Type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter. January 2017

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SGLT2 INHIBITORS

Monitoring: ADEs

Pain upon urination

Tenderness, swelling of genitals

Daily foot checks

Weight

BP

Renal function

Hypoglycemia

Warnings

Black Box Warning:

↑ amputations with canagliflozin

(6/1000 vs. 3/1000 with other medications)

Perineum necrotizing fasciitis “Fournier’s gangrene”

Pancreatitis

Canagliflozin: ↑ fracture risk, ↓ bone mineral density

Dapagliflozin: ↑ bladder cancer risk

Dapagliflozin, canagliflozin: acute kidney injury (AKI) requiring dialysis N Engl J Med. 2015;373:2117– 2128.

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EMPA-REG OUTCOME TRIAL

Empagliflozin’s Effect on Cardiovascular Outcomes in Type 2 Diabetes

Purpose: Determine empagliflozin’s effect vs. placebo on CV outcomes in patients with T2DM and existing CV events

Placebo run-in Empagliflozin 25 mg

Placebo


Randomization 1:1:1

Screening End treatment2 weeks 3.5-5 years

Empagliflozin 10 mg

N Engl J Med. 2015;373:2117– 2128.39


Follow up: 3.8 years

Participants

T2DM with existing cardiovascular disease (MI, CAD, unstable angina, stroke, PAD)

Mean age 63 yo, 73% Caucasian, 57% duration of diabetes >10 years, HbA1c 8.1%



ACEI/ARB: 81%, BB: 65%, ASA: 83%

N Engl J Med. 2015;373:2117– 2128.40


OutcomeEmpagliflozin


NNT


10.5% 12.1% 62

Death from CV causes 3.7% 5.9% 45

Death from any cause 5.7% 8.3% 38

HF hospitalization 2.7% 4.1% 71

HbA1c 0.54-0.60% Weight 2.0 kg SBP 5 mmHgEmpagliflozin:

Empagliflozin had increase in genital infections

N Engl J Med. 2015;373:2117– 2128.41


Empagliflozin reduces CV events in patients with T2DM with CVD

Conclusion

N Engl J Med. 2015;373:2117– 2128.42

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CANVAS TRIAL

Canagliflozin and cardiovascular and renal events in type 2 diabetesPurpose: Determine canagliflozin’s effect on CV and renal outcomes in T2DM patients with or at risk for CV events

Placebo run-in Canagliflozin 300 mg

Placebo

Screening End treatment2 weeks 126 weeks

Canagliflozin 100 mg (CANVAS-R patients may increase to 300 mg)

N Engl J Med. 2017;377:644– 657.43

Double-blinded667 sites in 30 countries2 trials, >10,000 patients

Outcomes• 25% reduction in MACE• 33% reduction in HF

hospitalizations

• HbA1c ↓ 0.58% • Weight ↓ 1.6 kg • SBP ↓ 3.93 mmHg

DECLARE-TIMI 58 TRIAL

Dapagliflozin’s and Cardiovascular Outcomes in Type 2 Diabetes

Purpose: Determine dapagliflozin’s effect vs. placebo on CV and renal outcomes in patients with T2DM

Placebo run-in

Placebo


Randomization 1:1:1

Screening End treatment4-8 weeks 3.5-5 years

Dapagliflozin 10 mg

N Engl J Med. 2018. ePub44

Patients followed up- In person every 6 months- By phone every 3 months


Follow up: 4.2 years

Participants

T2DM with existing cardiovascular disease (40.6%) or multiple risk factors (59.4%)

History of heart failure – 10%

Mean age 63 yo, 79% Caucasian, 57% duration of diabetes 11 years, HbA1c 8.3%



ACEI/ARB: 81%, BB: 52%, ASA: 75%

45N Engl J Med. 2018. ePub


OutcomeDapagliflozin


p value Hazard Ratio

Primary 1: MACE 8.8% 9.4% 0.17 0.93 (0.84-1.03)

Primary 2: Composite CV death or HF hospitalization

4.9% 5.8% 0.005 0.83 (0.73-0.95)

Death from CV causes 2.9% 2.9% 0.98 (0.82-1.17)

Death from any cause 6.2% 6.6% 0.93 (0.82-1.04)

HF hospitalization 2.5% 3.3% 0.73 (0.61-0.88)

Renal composite outcome 4.3% 5.6% 0.76 (0.67-0.87)

HbA1c 0.54-0.60% Weight 1.5 kg SBP 2.7 mmHgDapagliflozin:

46N Engl J Med. 2018. ePubLess serious adverse events 34.1% vs 36.2%; p<0.001


Dapagliflozin does not add or reduce CV events but does reduce CV death and hospitalization for heart failure and

may reduce adverse renal outcomes

Conclusion

N Engl J Med. 2015;373:2117– 2128.47

MECHANISM FOR CV BENEFIT

↓ Preload ↓ Afterload

↓ Aortic stiffness

↑ Ketone breakdown

SGLT2i

Diabetes Ther. 2018;9:919-926. Diabetes Obes Metab. 2017;19:1353-1362.

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Patient Case

Patient JK – 56 yo F

CC: “My sugars are still high”

PMH: T2DM x 7y, HTN, HFpEF, osteoporosis

A1c 7.7%

Medications

Metformin 1g BID

Levemir 10 units nightly

Trulicity 1.5 mg weekly

Lisinopril 10 mg daily

Vit D/Calcium supplement

FBG 7 day avg: 155

Vitals

Height 5’6

Weight 220 lbs

Blood Pressure 142/92 mmHg

What medication class would be best to start in this patient?

A. Sulfonylurea

B. Thiazolidinedione (TZD)

C. GLP-1 RA

D. DPP4i

E. SGLT2i

CARDIOVASCULAR BENEFIT TRIAL OUTCOMES Drug Brand Trial ↓ CV Outcome ↓ Mortality

FDA-approved CVD

indication

GLP-1 RAs

Liraglutide Victoza LEADER

Exenatide Bydureon EXSCEL X XDulaglutide Trulicity REWIND Complete Complete ?Semaglutide Ozempic SUSTAIN-6 X XLixisenatide Adlyxin ELIXA X X XAlbiglutide Tanzeum HARMONY X X

SGLT2is

Empagliflozin Jardiance EMPA-REG

Canagliflozin Invokana CANVAS XDapagliflozin Farxiga DECLARE-TIMI 58 X ?Erturgliflozin Steglatro VERTIS In progress In progress ?

Diabetes Care. 2018;41(Suppl. 1):S86–S104

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CLINICAL QUESTION

Could combining 2 drugs with cardiovascular benefits produce additive outcomes?

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COMBINATION THERAPY

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COMBINATION THERAPY: MECHANISM OF ACTION

Euglycemia

Cardio-protection

↑ Satiety, ↓ food intake

↓Gastric emptying and intestinal motility

↓Triglycerides

BothGLP-1 RAs SGLT2is

Key

↑ Glucose uptake

↓ insulin, ↑ glucagon

↑ insulin, ↓ glucagon

↓Ischemia and atherosclerotic

plaques

Natriuresis

↓ Plasma volume, preload, stretch

myocardium

Glucosuria

Vasodilation↓ BP, afterload,

and inflammation

↑ Ketogenesis

COMBINATION THERAPY

Anticipated Effect of Combination Therapy

Effect GLP-1 RAs SGLT2 inhibitors Combination

MACE

Glycemic Control

Insulin Sensitivity

Blood Pressure

Body Weight

Glucose Uptake

MACE: Major Adverse Cardiac Event

Postgraduate Medicine.

2017;129(7):686-697.

Diabetes Obes Metab.

2017;19:1353-1362.

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LITERATURE

DURATION-8

Exenatide vs. Dapagliflozin vs. Combination Therapy

With metformin

Started simultaneously

AWARD-10

Dulaglutide added onto existing SGLT2i therapy

With or without metformin

Started step-wise

55

Only 2 large trials involving combination therapy

DURATION-8 TRIAL

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8):

A 28 week, multicenter, double blind, phase 3, randomized controlled trial

Purpose: To compare the efficacy and safety of co-initiation a GLP-1 receptor agonist and SGLT2 inhibitor with exenatide or dapagliflozin alone

Exenatide

Exenatide 2 mg weekly + Dapagliflozin 10 mg daily

Randomization 1:1:1 End treatment28 weeks

Dapagliflozin

• Diet and exercise counseling

• Basal insulin therapy allowed for: •Weeks 8-12: FBG > 270 mg/dL•Weeks 12-20: 240 mg/dL•Weeks >20: 200 mg/dL

Lancet Diabetes Endocrinol. 2016;4:1004-16.56

Screening

2 weeks

Metformin >1500 mg/day

DURATION-8 TRIAL

Participants:

Background characteristics similar among groups except:

Less females in the exenatide group

Fewer Hispanic patients in the dapagliflozin group

Age: 54 yo

83% white

Weight: 90 kg

Duration of diabetes: 7.5 years

A1c: 9.3%

Blood pressure: 130/78 mmHg

Lancet Diabetes Endocrinol. 2016;4:1004-16.

57

DURATION-8 TRIAL

OutcomeExenatide +

Dapagliflozinn=193

Exenatide n=184

Dapagliflozinn=196

Exenatide + Dapagliflozin vs.

Exenatide


Dapagliflozin

HbA1c (%) -2.0 -1.6 -1.4 p=0.003 p<0.001

Weight (kg) -3.55 -1.56 -2.22 p<0.001 p<0.001

Weight loss >5% 33% 14% 20% p<0.001 p=0.001

Intent-to-treat population

Weight loss more significant among patients with HbA1c 8-9% than >9%.


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DURATION-8 TRIAL

Change in HbA1c from baseline Patients reaching HbA1c goals


59

DURATION-8 TRIAL

Change in weight from baseline


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DURATION-8 TRIAL

OutcomeExenatide +dapagliflozin

n=201

Exenatide n=190

Dapagliflozinn=207


Exenatide


Dapagliflozin

Systolic BP (mmHg)

-4.3 -1.2 -1.8 p=0.005 p=0.022

Per Protocol

No intergroup differences for diastolic blood pressure


61

DURATION-8 TRIAL

Strengths

Randomized, double blind trial

High external validity

Assessed HbA1c subgroups

Limitations

Short duration – 28 weeks

No placebo group

Hypoglycemia definition <54 mg/dL –strict

Treatment guidelines do not recommend simultaneous addition of 2 drugs

Utilized 2 drugs with no FDA indications for CV protection

Average BP at goal at baseline (<140/90 mmHg)


DURATION-8 TRIAL

Compared with either drug along, concomitant use of exenatide and dapagliflozin resulted in:

• Better glycemic control

• Weight loss

• Lower systolic blood pressure

• No increase in hypoglycemia

Conclusion


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AWARD-10 TRIAL

Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes: A 24-week, randomized, double blind, placebo-controlled trial

Purpose: To assess the safety and efficacy of adding once weekly dulaglutide to patients inadequately controlled on SGLT2is.

Dose stabilization

Dulaglutide 1.5 mg

Placebo

Double-blind, parallel arm 40 sites

Randomization 1:1:1Screening End treatment

12 weeks 24 weeks

Dulaglutide 0.75 mg

• Compliance assessed at clinic appointments at weeks 2,4,8,12,18,and 24 weeks

• Adjustments per standard of care


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AWARD-10 TRIAL

Inclusion Criteria

>18 years old

HbA1c 7.0-9.5%

BMI <45 kg/m2

Taking an SGLT2 inhibitor with or without metformin (>1500 mg/day, as tolerated) for at least 3 months

Exclusion Criteria

Type 1 Diabetes

Used any other glucose-lowering drug (other than SGLT2 inhibitor and metformin) 3 months prior to entry

Serum calcitonin >20 pg/mL

History of pancreatitis, ketoacidosis, hyperosmolar state or coma, recent CV event, active cancer


65

AWARD-10 TRIAL

Participants

Taking an SGLT2 inhibitor with or without metformin (>1500 mg/day, as tolerated) for at least 3 months

Baseline characteristics similar among groups

Age: 56-58.5 yo

89% white

Body weight: 90 kg

Duration of diabetes 8.8-10 years

A1c: 8

Blood pressure: 130/77 mmHg

95% on metformin

Patients on SGLT2 inhibitors for avg 3-6 months Lancet Diabetes Endocrinol. 2018;6:370-81.

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AWARD-10 TRIAL

HbA1c Change Proportion of Patients Reaching

HbA1c <7% and 6.5%


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AWARD-10 TRIAL

Bodyweight Reduction

Blood Pressure

Dulaglutide 1.5 mg

Placebo P value

Systolic -4.5 -1.4 0.021

Diastolic -1.1 -1.0 0.93

Blood Pressure

Dulaglutide 0.75 mg

Placebo P value

Systolic -3.2 -1.4 0.17

Diastolic -0.4 -1.0 0.47


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Blood Pressure Reduction

AWARD-10 TRIAL

Event Dulaglutide 1.5 mg Dulaglutide 0.75 mg Placebo

Pancreatic event 0 0 0

Cardiovascular event 0 0 3 (2%)MI: 2,UA: 1

Renal and Urinary Disorders 1(1%) 3 (2%) 4 (3%)

Treatment emergent adverse events (>5%)

- GI disorders 46 (32%) 29 (21%) 24 (17%)

Amputation, DKA 0 0 0

Genital infection 0 0 1 (1%)

Hypoglycemia 5 (4%) 5 (4%) 4 (3%)


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AWARD-10 TRIAL

Strengths

Randomized, double blind trial

Used step-wise addition of medications per guideline recommendations

Limitations

Short duration

Small external validity due to inclusion criteria of HbA1c <9.5%

Patients on differing doses of SGLT2 inhibitors

Effect of SGLT2 inhibitors may still effect HbA1c reduction


AWARD-10 TRIAL

Adding dulaglutide to SGLT2is improved glycemic control and decreased weight and

systolic blood pressure

Conclusion


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COMBINATION THERAPY

Euglycemia

Cardio-protection

↑ Satiety, ↓ food intake

↓Gastric emptying and intestinal

motility

↓Triglycerides

BothGLP-1 RAs SGLT2is

Key

↑ Glucose uptake↓ insulin,

↑ glucagon

↑ insulin, ↓ glucagon

↓Ischemia and atherosclerotic

plaques

Natriuresis

↓ Plasma volume, preload, stretch

myocardium

GlucosuriaVasodilation

↓ BP, afterload, and inflammation

↑ Ketogenesis

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SYNERGISTIC, ADDITIVE, OR LESS THAN ADDITIVE?

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COMBINATION THERAPY

Trial Study Groups HbA1c Effect

DURATION-8Exenatide Dapagliflozin Combination

-1.6% -1.4% -2.0%

AWARD-10Placebo-0.54%

Dulaglutide 0.75 mg-1.21%

Dulaglutide 1.5 mg -1.34%

HbA1c Reduction alone vs. placebo

GLP-1 RAs – 0.6-1.4% SGLT2is – 0.5-1.2%

May not be the cause of CV outcomes

GLP-1 RA SGLT2 i

↑ glucagon

Less than additive

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COMBINATION THERAPY

Trial Study Groups Weight Effect


-1.54 -2.19 -3.55

AWARD-10Placebo

-2.1Dulaglutide 0.75 mg


-3.1

Body Weight Reduction alone vs. placebo

GLP-1 RAs – 0.3 to -2.3 kg SGLT2is – -1.3 to -3.0 kg GLP-1 RA SGLT2 i

Slow gastric emptying

Suppress appetite

Water loss

Close to additive

75

COMBINATION THERAPY

Trial Study Groups Blood Pressure Effect


-1.2 -1.8 -4.0%

AWARD-10Placebo



-4.6

Blood Pressure Reduction alone vs. placebo

GLP-1 RAs – 2.0 to 3.1 mmHg SGLT2is – 2.6 to 7.5 mmHg

Synergistic

GLP-1 RA SGLT2 i

Vasodilation

↓ intravascular volume

Natriuresis

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MY CONCLUSION

Some SGLT2is and GLP-1 RAs independently reduce CV events by reducing blood pressure, weight, and HbA1c simultaneously

In combination they:

Synergistic – SBP

Additively – Weight

Less than additive – HbA1c

Do not increase adverse events

Need CV outcome trials to prove their benefit long term

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CONCERNS

Sustainability Short trials to date

Generalizability to other patient populations Longer duration of disease Not at current high CV risk Elderly Less obese patients

Cost Barrier to many patients Differing insurance plans Prescription Assistance Programs (PAP) and coupons are available

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14

CVOT LIMITATIONS

Participants differ among trials

Trial follow-up <5 years, may not see CV benefit or risks

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FUTURE TRIALS

In progress

PIONEER-4: Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

“Is it worth it?”

Time

Resources

Many neutral results

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RECOMMENDATION FOR CV RISK REDUCTION

Address multiple CV risk factors at once

Step-wise addition of antidiabetics

* If these options are not on formulary, choose other SGLT2i or GLP-1RA

In patients with clinical ASCVD or high risk for CVD

Albuminuria, hypertension, left ventricular systolic or diastolic dysfunction

81

Metformin ER 1g BID Liraglutide 1.8 mcg

dailyEmpagliflozin 10 mg

daily

KEY TAKE AWAYS

Diabetes is an individual risk factor for ASCVD; there is need to prevent CV events

Some GLP-1 RAs and SGLT2is have proven to reduce CV events

Empagliflozin and liraglutide are FDA-approved to reduce the risk of CV events in patients with T2DM

↓ CV mortality and composite CV Outcome

Reasonable to consider these first or second line in patients at high risk for CV events

The 2 drug classes have different mechanisms that complement each other

May have an additive effect of further reducing CV outcomes

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ASSESSMENT QUESTION

What is the only GLP1-RA with an FDA indication for reduction of CV events in patients with ASCVD and T2DM

A. Bydureon (exenatide)

B. Victoza (liraglutide)

C. Trulicity (dulaglutide)

D. Byetta (exenatide)

83

ASSESSMENT QUESTION

84

What are the only SGLT2 inhibitors with FDA indications for reduction of CV events or CV mortality in patients with T2DM

A. Jardiance (empagliflozin)

B. Invokana (canagliflozin)

C. Farxiga (dapagliflozin)

D. A + B

E. B + C

2/11/2019

15

POLL

What is your favorite second line antidiabetic class after metformin for a Type 2diabetic patient without complications?

A. Sulfonylurea

B. DPP4 Inhibitor

C. GLP-1 RA

D. SGLT2 inhibitor

E. Other

85

ACKNOWLEDGEMENTS

Committee:

April Hinds, PharmD, BCACP

Catlin Grisham-Takac, PharmD, BCPS

86

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GETTING TO THE HEART OF TYPE 2 DIABETES MANAGEMENT: AN UPDATE ON

CARDIOVASCULAR OUTCOME TRIAL RESEARCH

KATHRYN LITTEN, PHARMDPGY2 AMBULATORY CARE RESIDENTCOMMUNITYCARE HEALTH CENTERUNIVERSITY OF TEXAS AT AUSTIN COLLEGE OF [email protected] 88

powerpoint presentation€¦ · 2016;133(24):2459-2502. figure: diabetes spectrum....

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