Cardiovascular Outcome Trials of

Diabetes Medications: Translating

Results into Practice

Carol Hatch Wysham, MD

Clinical Professor of Medicine

University of Washington

Rockwood Center for Diabetes and Endocrinology

Spokane, Washington

Presenter Disclosure Information

In compliance with the accrediting board policies, the American

Diabetes Association requires the following disclosure to the

participants:

Carol H. Wysham, MD

Consultant/Advisory Panel: Abbott, Astra Zeneca, Boehringer Ingelheim,

Janssen, Novo Nordisk, Sanofi

Speaker’s Bureau: Astra Zeneca, Boehringer Ingelheim, Insulet, Janssen,

Novo Nordisk, Sanofi

Stroke2- to 4-fold increase in cardiovascular mortality and stroke5Diabetic

Retinopathy

Leading cause

of blindness

in adults1,2

Diabetic

Nephropathy

Leading cause of

end-stage renal

disease3,4

Diabetic

Neuropathy

Leading cause of

non-traumatic

lower extremity

amputations7,8

Cardiovascular

Disease

8/10 individuals with

diabetes die from

CVD

Complications of Diabetes

ERFC JAMA 2015.

Diabetes & prior CVD begets premature mortality

Improvements in Diabetes-Related Complications

in the USA, 1990-2010

Acute myocardial infarction

Adapted from Gregg EW, et al. N Engl J Med 2014;370:1514–1523.

ADA Recommendations for Statin

Therapy1,2

Age,

y

No Risk Factors ASCVD Risk

Factorsa

With ASCVD

< 40 None Moderate or

high intensity

High intensity

40-75 Moderate intensity High intensity High intensity

> 75 Moderate intensity Moderate or

high intensity

High intensity

If ACS is present and LDL-C ≥ 50 mg/dL or statin intolerant, use moderate-intensity

statins + ezetimibe.• For every 39-mg/dL reduction in LDL-C3: 21% reduction in MACE, 9% reduction

in all-cause mortality

• PCSK9 inhibitors may be considered in patients at high risk of ASCVD events

who are intolerant of high-intensity statin therapy1

a LDL-C ≥ 100 mg/dL, HTN, smoking, chronic kidney

disease, albuminuria, and family history of premature

ASCVD.b ≈ 1% annual risk of major CV event; BL LDL-C = 127.8

mg/dL, diabetes prevalence ≈ 6%.4

1. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135. 2. Stone NJ, et al. Circulation. 2014;129(25 suppl 2):S1-S45.

3. Fox CS, et al. Diabetes Care. 2015;38:1777-1803.4.

Pharmacologic Interventions

•Treatment for hypertension should include drug classes demonstrated

to reduce CV events in patients with diabetes: A

• ACE Inhibitors

• Angiotensin receptor blockers (ARBs)

• Thiazide-like diuretics

• Dihydropyridine calcium channel blockers

Cardiovascular Disease and Risk Management:

Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S86-S104

Hypertension/BP Control: Recommendations SBP target: <140 most, <130 select but

relax in elderly (? <150 when >80 yrs)

• For most outcomes, risk reduction max <140

SBP1

• <130 SBP further reductions in high risk for CVD,

stroke, retinopathy and albuminuria1,3

• BP < 130/70 associated with increased mortality

in older adults2

Emdin et al JAMA 2015 2 ADA Standards of Care 2016, 3ADA Standards of care 2018

Ali MK et al. N Engl J Med 2013;368:1613-1624.

Distribution of Risk Factors for Vascular

Complications among U.S. Adults with

Diabetes, 1999–2010. Diabetes and Heart Failure

• Second most common presentation of heart disease in diabetes (after peripheral vascular disease)

• 12% of all cases of HF attributable to DM

• RF: older, long duration DM, insulin treatment, poor glycemic control

• When coexists with HF, diabetes associated with 53% higher risk of hospitalization and 50% higher mortality. Median survival 50% in 5 years.

• Costs in 2012: 31 billion, primarily hospitalizations

• #1 reason for hospitalization in those > 65 yrsMcDonald MR et al Eur Heart J, 2008

Heart Failure after MI Associated with

High Mortality

• Retrospective chart review of all patients with first myocardial infarction, without previous diagnosis of heart failure – N = 2596

• mean follow up 7.6 years

• Results:

• 902 developed heart failure (58/1000 pt years)• Risk factors: older, female, HTN, DM

• 535 developed recurrent MI

• 1116 died• >50% of deaths occurred after diagnosis of HF (5-fold higher in those

without HF)

Gerber Y et al. Circ Heart Fail. 2016;9:e002460. DOI: 10.1161/CIRCHEARTFAILURE.115.002460

Cardiovascular Risk in Type 2 Diabetes:

Intensive vs less intensive glycemic control

Cardiovascular events Mortality

ACCORD

ADVANCE

UKPDS

VADT

1. Bergenstal RM et al. Am J Med 2010;123:374.e18; ; 2. Scirica BM et al. N Engl J Med 2013;369:1317-26; 3. White WB et al. N Engl J Med 2013;369:1327-35.

4.Green JB et al. N Engl J Med 2015;373:232-42 5. Pfeffer MA et al. N Engl J Med 2015;373:2247-57; ; 6. Zinman B et al. N Engl J Med 2015;373:2117-28;

7. Marso SP et al. N Engl J Med 2016; epub ahead of print.

Completed and ongoing CVOTs

William T. Cefalu et al. Dia Care 2018;41:14-31

©2018 by American Diabetes Association

SAVOR-TIMI 53 (DPP4i - saxagliptin)2

EXAMINE (DPP4i - alogliptin)3

TECOS (DPP4i - sitagliptin)4

ELIXA (GLP-1 RA - lixisenatide)5

LEADER (GLP-1RA – liraglutide)7

EXSCEL (GLP-1RA – exenatide QW)

SUSTAIN-6 (GLP-1RA – semaglutide)

EMPA-REG OUTCOME (SGLT2i –empagliflozin)6

CANVAS (SGLT-2i – canagliflozin)

Cardiovascular Outcome Trials: Reported Studies

to DateCardiovascular events Mortality

1. Bergenstal RM et al. Am J Med 2010;123:374.e18; ; 2. Scirica BM et al. N Engl J Med 2013;369:1317-26; 3. White WB et al. N Engl J Med 2013;369:1327-35.

4.Green JB et al. N Engl J Med 2015;373:232-42 5. Pfeffer MA et al. N Engl J Med 2015;373:2247-57; ; 6. Zinman B et al. N Engl J Med 2015;373:2117-28;

7. Marso SP et al. N Engl J Med 2016; epub ahead of print.

Approved SGLT-2 Inhibitors With Proven Benefit on

Cardiovascular Outcomes in Prospective RCTs (Rates per

100 patient-years)

Em

pag

liflo

zin

(EM

PA

-RE

G)1

1. Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

2. Neal B, et al. N Engl J Med. 2017; DOI: 10.1056/NEJMoa1611925

.

012345

EMPA PBO

RR: -14%

RR: -35%RR: -38%

RR: -32%

012345

CANA PBO

RR: -14%

MACEHF

Hospitalization

CV

Mortalit

y

Can

aglif

lozi

n(C

AN

VA

S)2

RR: -9%NSRR: -11%NS

RR: -36%

Total

Mortalit

y

Approved GLP-1 Receptor Analogues With Proven

Benefit on Cardiovascular Outcomes in Prospective

RCTs (Rates/100 pt years)L

irag

luti

de

(LE

AD

ER

)1

.1 Marso SP, et al. N Engl J Med. 2016;375:311-322

32 Marso SP, et al. N Engl J Med. 2016;375:1834-1844.

012345

LIRA PBO

All-cause

RR: -13%

RR: -13%NS RR: -

22%

RR: -15%

MACE HF

Hospitalization

CV

Mortality

012345

SEMA PBORR: -26%

Sem

aglu

tid

e(S

US

TA

IN-6

)2

RR:-2% ns-

RR: +5%NS

RR: + 11NS

Number Needed to Treat to

Avoid One Event

LEADER EMPA-REG

3-point MACE 53 62

CVD Death 77 45

CHF Hospitalization NA 38

1. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 2. Marso SP, et al. N

Engl J Med. 2016;375:311-322

.

CVOT: Review of Primary and Secondary

Outcomes

0.87

Baseline Characteristics of CV Outcomes Trials

(SGLT-2 Inhibitors and GLP-1 RA)

EMPA-REG CANVAS ELIXA LEADER SUSTAIN EXSCEL

Mean age, y 63 63 60 64 65 62

Diabetes duration, y 12 14 9 13 14 12

% with prior HF 10 14 22 14 24 16

% with prior CVD 100 66 100 81 83 73

% with CKD 3+ 25 20 23 25 25 22

HbA1c, % 8.1 8.2 7.6 8.7 8.7 8.0

Statin use, % 77 75 64 75 73 73

Premature

discontinuation (%)25 29 25 NR (17) 20 44

Antihyperglycemic

therapy, %

• MET 77

• SU 43

• TZD 4

• INS49

• MET 77

• SU 43

• TZD NR

• INS 50

• MET 66

• SU 33

• TZD 2

• INS 39

• MET 76

• SU 50

• TZD 9

• INS 45

• MET 73

• SU 43

• TZD 2

• INS 20

• MET 77

• SU 37

• TZD 4

• INS 46

Adapted from: Standl E, et al. Circ Res. 2016;118:1830-1843.

ORIGIN: Composite Outcomes &

their Components

HR (95% CI) P Insulin Standard

/100 py /100 py

1st Coprimary 1.02 (0.94, 1.11) 0.63 2.94 2.85

2nd Coprimary 1.04 (0.97, 1.11) 0.27 5.52 5.28

Microvascular 0.97 (0.90, 1.05) 0.43 3.87 3.99

Death 0.98 (0.90, 1.08) 0.70 2.57 2.60

MI 1.02 (0.88, 1.19) 0.75 0.93 0.90

Stroke 1.03 (0.89, 1.21) 0.69 0.91 0.88

CV Death 1.00 (0.89, 1.13) 0.98 1.57 1.55

CHF Hospital 0.90 (0.77, 1.05) 0.16 0.85 0.95

Revascularized 1.06 (0.96, 1.16) 0.24 2.69 2.52

0.5 1 2Favors StandardFavors Insulin

HR

HRNEJM 2012;367:319

0

2

4

6

8

10

12

0 3 6 9 12 15 18 21 24 27 30

DEVOTE: Degludec vs Glargine

Time to first 3-point MACE

Full analysis set; Cox regression analysis accounting for treatment. Analysis includes events between randomization date and follow-up date.

Patients without an event are censored at the time of last contact (phone or visit)

EAC, Event Adjudication Committee; N, number of patients at risk; PYO, patient-years of observation

HR: 0.91[0.78; 1.06]95% CI

Non-inferiority confirmedp<0.001

Patients

with a

n e

vent

(%)

Insulin degludec (N) 3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217

IGlar U100 (N) 3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205

Time to first EAC-confirmed event (months)

IGlar U100

Insulin

degludec 356 patients

325 patients

MicrovascularOutcomes

STUDY Nephropathy (HR) Retinopathy (HR) Amputation (HR)

EMPA-REG 0.61 NR 0⍏

CANVAS 0.60 NR 1.97⍏

LEADER 0.78 1.15* NR

SUSTAIN-6 0.64 1.76* NR

Microvascular Complications in the CVOT studies

* Enrolled patients with higher A1c – monitored retinopathy as event of interest⍏Events/1000 patient years 6.5/1000 in treatment groups in both studies. Differences noted in placebo

event rate. EMPA – not collected during study

• In the SUSTAIN study: 79 events/3297 pts. 83% gave hx of DR, 29% hx of PDR

• In the CANVAS study: 125 events/10 ,142 pts. 71% “minor”. Highest with hx of amputation

& PVD

OtherAdverse Events of

Interest

CANVAS Program: Fractures• Despite all studies showed a lower A1c with active

treatment, only LEADER reported lower risk of

hypoglycemia:

• Confirmed: HR 0.80

• Severe: HR 0.69

Hypoglycemia

• In the studies with GLP-1 RA, the adverse profile was as expected: GI SE, injection site reactions (n = 27,389) .

• In LEADER, there was increase in gallbladder disease

• Despite increases in lipase and amylase, there was no evidence of increase in risk for pancreatitis nor pancreatic cancer.

• There was no evidence of increased risk for medullary cancer of the thyroid

• In the studies with SGLT-2 inhibitors, there was increased risk for genital mycotic infections and symptoms of volume depletion (n = 17,162)

• Volume depletion was reported in 26 and 17/1000 pt-years in CANVAS and EMPA-REG respectively

• There was no increase in risk for UTI, DKA, acute kidney injury, hyperkalemia.

Other Adverse Events of Interest

• Changes in traditional CVRF did not explain the outcomes in LEADER nor

EMPA-REG.

• EMPA-REF: Changes in Hct of about 5% (as a measure of volume status)

explained about 52% of the effect, followed by FBG at 22% and uric acid at

18%.

• Similar changes in Hct seen with canagliflozin, but not reported in CANVAS paper

• Direct anti-atherogenic actions postulated for CV effects of liraglutide

Mechanism of Action for Reduction of CV Risk

Potential Pathways Linking Empagliflozin With

CV Benefits: Volume and Hemodynamics

Sattar N et al. Diabetologia 2016; epub ahead of print.

Potential mechanisms of beneficial effect of glucagon-like peptide-1

(GLP-1) receptor agonists on reducing cardiovascular events.

Michael A. Nauck et al. Circulation. 2017;136:849-870

Copyright © American Heart Association, Inc. All rights reserved.

Carl

• 69 year old white male type 2 DM x15

yrs History of myocardial infarction,

albuminuria, neuropathy, and

nonproliferative retinopathy.

• ROS: chronic dyspnea on exertion.

diarrhea while on metformin

• SH: lives alone, doesn’t like to cook

• PE: Ht-75”, Wt-323 lbs, BMI-40.5, BP-

139/85 + S4 gallop, 2+ pedal edema,

absent pedal sensation

• A1c-8.0%, eGFR – 77, TC-165, TG-394,

HDL-C-33, LDL-C-53, ALT-21, UAE – 74

mg/gr Cr.

Glargine 64 units QHS

Aspart 20 units TID+ 1/20

for BG > 120

Losartan/HCT 50/12.5

Carvedilol 25 mg BID

Atorvastatin 80 mg

Fish oil 2000 mg BID

ASA 81 mg daily

What is your A1c goal for Carl?

A.<6.0%

B.<6.5%

C.<7.0%

D.<7.5%

E. <8.0%

more stringent

less stringent

Patient attitude and expected treatment efforts highly motivated, adherent,

excellent self-care capacities

less motivated, non-adherent,

poor self-care capacities

Risks potentially associated with hypoglycemia and other drug adverse effects

low high

Disease duration newly diagnosed long-standing

Life expectancy long short

Important comorbidities absent severe few / mild

Established vascular complications absent severe few / mild

Readily available limited

Usually not modifiable

Potentially modifiable

HbA1c7%

PATIENT / DISEASE FEATURES

Approach to the management of hyperglycemia

Resources and support system

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Consider less intensive glucose targets in T2DM with CVD

What is your primary concern for Carl?

A.Lower his A1c

B.Lower his triglycerides

C.Weight management

D.Lower his risk for recurrent cardiovascular

events &/or death from CVD

In addition to lowering the dose of insulin,

what would you suggest for improving his

glycemic control?

A.Add glimepiride

B.Add a DPP-4 inhibitor

C.Add liraglutide

D.Add SGLT-2 inhibitor.

E. Suggest bariatric surgery

Treatment considerations for Carl

• Signs of CHF and adequate GFR – good candidate for SGLT-2 inhibitor

• If SGLT-2 inhibitor is started:

– Minimize hypoglycemia – consider 20 - 30% reduction in insulin dose (both basal and prandial)

– DC HCTZ due to expected 5+ mmHg reduction in BP with SGLT-2 inhibitor

– Encourage increased fluid intake

– Advise about risk for balantitis, if not circumsized

Janice

• A 62-year-old woman with a 14

year history of T2D is seen for

diabetes management. She has

history of

Right CVA 6 months ago. She has

a 40 pack-year history of smoking,

but quit after CVA.

• BP 142/90, BMI 36 kg/m2

• PE: unremarkable

• Labs: HbA1c 8.5%, eGFR 40

mL/min/1.73m2, LDL 90, HDL 37,

TG 224; ALT normal; UACR 45

• SMBGs high 100s AM, 200s rest of

the day

Medications

• metformin 1000 mg

BID

• glimepiride 2 mg BID

• glargine insulin 65

units at bedtime

• lisinopril 20 mg daily

• HCTZ 25 mg daily

• atorvastatin 40 mg

daily

• ASA 81 mg daily

What is your A1c goal for

Janice?

A.<6.0%

B.<6.5%

C.<7.0%

D.<7.5%

E. <8.0%

What is the best next step to improve glycemic

control?

A. Increase glimepiride to 4 mg BID

B. Add linagliptin 5 mg daily

C. Add lispro with each meal

D. Add canagliflozin 100 mg daily

E. Add liraglutide up to 1.8 mg daily

Treatment Considerations for Janice

• Due to age and serious comorbidities, I would be satisfied with an A1c in the 7’s.

• With her low GFR, I would opt for substituting liraglutide for glimepiride

– Ensure up to date on eye exam.

– Advise about GI SE: slow titration

– Advise about risk for gallbladder disease

• With history of CVA, lower target BP might be indicated, if tolerated

– Consider an orthostatic BP/P

– Helpful to know the carotid anatomy

• Consideration for increasing atorvastatin vs adding ezetimibe

Jacinta

• 58 year old Hispanic female with type 2

DM x 6 yrs, and recent diagnosis of PVD

and small, healing noninfected foot

ulcer.

• ROS: Neg

• SH: Nonsmoker. Works as a manager

for the state

• PE: Ht-65”, Wt-166 lbs, BMI- , BP-139/88

1+ pedal edema, diminished pedal

sensation

• A1c-6.8%, eGFR – 75, TC-137, TG-238,

HDL-C-36, LDL-C-63, ALT-21, UAE – 155

mg/gr Cr.

Metformin 1000 mg BID

Canagliflozin 300 mg QD

Lisinopril 20 mg

Metoprolol 50 mg BID

Atorvastatin 40 mg

Fish oil 2000 mg BID

Aspirin 81 mg QD

What is your A1c goal for

Jacinta?

A.<6.0%

B.<6.5%

C.<7.0%

D.<7.5%

E. <8.0%

What is your primary concern for Jacinta?

A.Lower her triglycerides

B.Weight management

C.Lower her risk for recurrent cardiovascular

events &/or death from CVD

D.Management of her foot ulcer

What would you do with her

medications?

A.Nothing

B.Change canagliflozin to empagliflozin

C.Change canagliflozin to liraglutide

D.Stop metoprolol and continue other

medications.

Albert

• 70 year old white male type 2

DM x11 yrs, history of stent

placement after a myocardial

infarction 2 years ago. He

denies hypoglycemia. He has

Medicare Part D

• ROS: Neg

• SH: lives with his wife.

Nonsmoker

• PE: Ht-71”, Wt-244 lbs, BMI- 34,

BP-132/70 1+ pedal edema,

normal pedal sensation

• A1c-6.9%, eGFR – 57, TC-127,

TG-188, HDL-C-36, LDL-C-63,

ALT-21, UAE – 74 mg/gr Cr.

Degludec 44 units QHS

Aspart15 units TID+ 1/20

for BG > 120

Losartan 50

Amlodipine 5 mg

Atorvastatin 80 mg

Fish oil 2000 mg BID

Clopidogrel 75 mg daily

What is your A1c goal for

Albert?

A.<6.0%

B.<6.5%

C.<7.0%

D.<7.5%

E. <8.0%

What is your primary concern for Albert?

A.Lower his A1c

B.Lower his triglycerides

C.Weight management

D.Lower his risk for recurrent cardiovascular

events &/or death from CVD

Is he a candidate for addition of a

GLP-1 RA or SGLT-2 inhibitor?

A.No, his A1c is at target

B.No, they are too expensive

C.Yes, add liraglutide

D.Yes, add an SGLT-2 inhibitor

Treatment considerations for

Albert

• He would be a candidate for either SGLT-2

inhibitor or GLP-1 receptor agonist

• Cost can be managed by using lower doses:

– Do not titrate > 1.2 mg of liraglutide

– Use ½ tablet of max dose of empagliflozin or

canagliflozin

Cost of Liraglutide vs SGLT-2

Inhibitors

Drug Lowest cost for 30

days

Liraglutide 1.8 mg $993/662 (1.2 mg)

Empagliflozin 25 mg $415/208 (1/2 tab)

Canagliflozin 300 mg $443/222 (1/2 tab)

Source: GoodRx.com for zip 99203, accessed 9/11/17

• For patients with type 2 diabetes who have ASCVD, on lifestyle and metformin therapy, it is recommended to incorporate an agent with strong evidence for cardiovascular risk reduction, especially those with proven benefit on both major adverse cardiovascular events and cardiovascular disease

ADA Standards of Care 2018

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator placebo placebo placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017

Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND

GLP1-RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide

Comparator placebo placebo placebo placebo placebo

N 16,500 14,000 6,000 5,400 8,300

Results 2016 2015 2016 2018 2019

Study EMPA-REG CANVAS DECLARE NCT01986881

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin

Comparator placebo placebo placebo placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020

Large CV Outcomes Trials in Diabetes (Non-Insulin)

Rates of All Complications of Diabetes are

Decreasing

Adapted Gregg E et al.N Engl J Med. 2014.

Summary: Lowering Risk for CVD

events in Diabetes • Clear evidence CVD/mortality in T2DM over several decades, but

there remains a large gap over the risk for patients without diabetes

– Better management of CVD risk factors have a major role, but

many sub-optimally treated

• BP and LDL-C reduction > glucose reduction

• Smoking reduction

• Best time to prevent CVD with glucose control is at diagnosis

• Cardiovascular outcome trials show safety of DPP-4 inhibitors, insulin

glargine, insulin degludec, lixisenatide and exenatide QW

• Data from cardiovascular outcome trials support role of SGLT-2

inhibitors (empagliflozin and canagliflozin) and 2 of the long-acting

GLP-1 receptor agonists (liraglutide and semaglutide) for reduction of

CVD events in patients with established CVD

Differences within Class: GLP-1 RA

• Only two with demonstrated CV benefit:

liraglutide and semaglutide

• Exenatide QW – barely missed significance –

likely related to high medication

discontinuation

• Lixisenatide – ND – likely related to short

duration of action

Differences within Class: SGLT-2

inhibitor

• Greater impact on CV death with

Empagliflozin – in part related to higher CV

risk

– Impact on primary endpoint and CHF similar

• Significant increase in amputations and

traumatic fractures seen in CANVAS trial

– Both likely related to greater risk for volume

depletion reported in CANVAS (26/1000 pt-yr)

compared to EMPA-REG (18/1000 pt yr)

Metformin

SGLT-2iGLP-1

RA

Ensure

HbA1c Target

Ensure

effective

RF control

Type 2 DM & ASCVD: Reducing Risk

Adult with T2D,

microalbuminuria,

obesity,

HTN,

CAD

Successful

obesity

management

GFR ≥ 45

Yes No

Special precautions:

• retinopathy, especially with semaglutide

• PVD, especially with canagliflozin