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TRANSCRIPT
2/11/2019
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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
2
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
3
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)
4
ASSESSMENT QUESTION
5
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 AND DIABETES
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 AND DIABETES
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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CARDIOVASCULAR DISEASE AND DIABETES
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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13
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
15
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
GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS
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
GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS
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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CARDIOVASCULAR OUTCOME TRIALS
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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
Double-blinded610 sites in 28 countries
Randomization 1:1Screening End treatment2 weeks 1.6 years 30 days
Lancet. 2018; 392:1519–29.
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HARMONY OUTCOMES TRIAL
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%
~74% of patient on metformin, 59% on insulin
CV medications: statins and antihypertensives - similar among groups
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Lancet. 2018; 392:1519–29.
HARMONY OUTCOMES TRIAL
OutcomeAlbiglutide
n= 4731Placebo n= 4732
P value
Primary compositeoutcome
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.
HARMONY OUTCOMES TRIAL
Albiglutide reduces CV events in patients with T2DM with ASCVD
Conclusion
30
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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CARDIOVASCULAR OUTCOME TRIALS
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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
Double-blinded590 sites in 42 countries
Randomization 1:1:1
Screening End treatment2 weeks 3.5-5 years
Empagliflozin 10 mg
N Engl J Med. 2015;373:2117– 2128.39
EMPA-REG OUTCOME TRIAL
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%
~74% of patient on metformin, 48% on insulin
CV medications: statins and antihypertensives - similar among groups
ACEI/ARB: 81%, BB: 65%, ASA: 83%
N Engl J Med. 2015;373:2117– 2128.40
EMPA-REG OUTCOME TRIAL
OutcomeEmpagliflozin
n= 4687Placebo n= 2333
NNT
Primary compositeoutcome
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
EMPA-REG OUTCOME TRIAL
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
Double-blinded882 sites in 33 countries
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
DECLARE-TIMI 58 TRIAL
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%
~82% of patient on metformin, 41% on insulin
CV medications: statins and antihypertensives - similar among groups
ACEI/ARB: 81%, BB: 52%, ASA: 75%
45N Engl J Med. 2018. ePub
DECLARE-TIMI 58 TRIAL
OutcomeDapagliflozin
n= 8582Placebo n= 8578
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
DECLARE-TIMI 58 TRIAL
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.
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DURATION-8 TRIAL
OutcomeExenatide +
Dapagliflozinn=193
Exenatide n=184
Dapagliflozinn=196
Exenatide + Dapagliflozin vs.
Exenatide
Exenatide + Dapagliflozin vs.
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%.
Lancet Diabetes Endocrinol. 2016;4:1004-16.
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DURATION-8 TRIAL
Change in HbA1c from baseline Patients reaching HbA1c goals
Lancet Diabetes Endocrinol. 2016;4:1004-16.
59
DURATION-8 TRIAL
Change in weight from baseline
Lancet Diabetes Endocrinol. 2016;4:1004-16.
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DURATION-8 TRIAL
OutcomeExenatide +dapagliflozin
n=201
Exenatide n=190
Dapagliflozinn=207
Exenatide + Dapagliflozin vs.
Exenatide
Exenatide + Dapagliflozin vs.
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
Lancet Diabetes Endocrinol. 2016;4:1004-16.
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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)
Lancet Diabetes Endocrinol. 2016;4:1004-16.62
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
Lancet Diabetes Endocrinol. 2016;4:1004-16.
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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
Lancet Diabetes Endocrinol. 2018;6:370-81.
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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
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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
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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
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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
DURATION-8Exenatide Dapagliflozin Combination
-1.54 -2.19 -3.55
AWARD-10Placebo
-2.1Dulaglutide 0.75 mg
-2.6Dulaglutide 1.5 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
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COMBINATION THERAPY
Trial Study Groups Blood Pressure Effect
DURATION-8Exenatide Dapagliflozin Combination
-1.2 -1.8 -4.0%
AWARD-10Placebo
-1.4Dulaglutide 0.75 mg
-3.2Dulaglutide 1.5 mg
-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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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
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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)
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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
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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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ACKNOWLEDGEMENTS
Committee:
April Hinds, PharmD, BCACP
Catlin Grisham-Takac, PharmD, BCPS
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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