california chapter of the american association of clinical...

California Chapter of the American Association of

Clinical Endocrinologists AACE

Presents:

Hot Topics in Diabetes and Endocrinology for

Primary Care

Cardiovascular Outcome Studies, Is It Time

for a Paradigm Shift?

Jennifer Han, MD, FACE

Assistant Clinical Professor

UCLA - David Geffen School of Medicine

Division of Endocrinology

No Disclosures

Case 1:

• A 55 year old male with a past medical history of coronary

artery disease status post stent placement and 5 year

history of diabetes presents to your clinic. A1C is 8.2%.

Left ventricular ejection fraction is within normal limits.

Creatinine is 1.1 with eGFR 68.

He is currently on metformin therapy

What would be the next best agent to add on?

• A. basal insulin

• B. empagliflozin

• C. sitagliptin

• D. rosiglitazone

Case 2:

• A 63 year old female with PMH of CVA and10 year history

of diabetes presents to your clinic. A1C is 7.8%. LVEF is

28%. On PE, lungs are clear to auscultation and there is

no evidence of edema/volume overload. Creatinine is 0.9

with eGFR 72.

What would be the agents that you would you avoid?



• C. sitagliptin


Overview

• Review diabetes and cardiovascular disease

• Brief overview of non-insulin medications available to treat

diabetes

• Review of key studies in the cardiovascular outcome trials

• Case presentations

Diabetes and Cardiovascular Disease

• Diabetes is the leading cause of cardiovascular morbidity

and mortality worldwide

– Diabetes imparts a 2-3 fold increased risk of cardiovascular

disease

– 10% Americans have diabetes and 65% of them will die from CV

disease

• People with diabetes have a 8 year less cardiovascular

disease free life expectancy for adults older than 50 years

compared to people without diabetes

• CV disease is the most likely cause of hospitalization in

patients with diabetes

Available Drugs for the Treatment of

T2DM

So many choices …

Non-insulin Agents Available for Treatment of Type 2 Diabetes

Class Primary Mechanism of Action Agent Available as

-Glucosidase

inhibitors

• Delay carbohydrate

absorption from intestine

Acarbose Precose or generic

Miglitol Glyset

Amylin analogues

• Decrease glucagon

secretion

• Slow gastric emptying

• Increase satiety

Pramlintide Symlin

Biguanides

• Decrease HGP

• Increase glucose uptake in

muscle

Metformin Glucophage or generic

Bile acid

sequestrants

• Decrease HGP?

• Increase incretin levels?Colesevelam WelChol

DPP-4 inhibitors

• Increase glucose-

dependent insulin secretion

• Decrease glucagon

secretion

Alogliptin Nesina

Linagliptin Tradjenta

Saxagliptin Onglyza

Sitagliptin Januvia

Dopamine-2

agonists

• Activates dopaminergic

receptorsBromocriptine Cycloset

HGP=hepatic glucose production. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1-48.

Noninsulin Agents Available for Treatment of Type 2 Diabetes

Class Primary Mechanism of Action Agent Available as

Glinides • Increase insulin secretionNateglinide Starlix or generic

Repaglinide Prandin

GLP-1 receptor

agonists

• Increase glucose-dependent

insulin secretion

• Decrease glucagon secretion


• Increase satiety

Exenatide Byetta

Exenatide XR Bydureon

Liraglutide Victoza

Albiglutide Tanzeum

Semaglutide Ozempic

Dulaglutide Trulicity

Lixisenatide Lyxumia *

SGLT2 inhibitors• Increase urinary excretion of

glucose

Dapagliflozin Farxiga/Forxiga

Canagliflozin Invokana

Empagliflozin Jardiance

Iprafliflozin Suglat

Sulfonylureas • Increase insulin secretion

Glimepiride Amaryl or generic

Glipizide Glucotrol or generic

GlyburideDiaeta, Glynase,

Micronase, or generic

Thiazolidinediones

• Increase glucose uptake in

muscle and fat

• Decrease HGP

Pioglitazone Actos

Rosiglitazone Avandia

Combination Agents Available for the Treatment of Type 2 Diabetes

Class Added Agent Available asDPP4i + SGLT2i Saxagliptin/Empagliflozin Glyxambi

Metformin + DPP-4 inhibitorAlogliptin Kazano

Linagliptin Jentadueto

Saxagliptin Kombiglyze XR

Sitagliptin Janumet

Metformin + glinideRepaglinide Prandimet

Metformin + SGLT2 Canagliflozin Invokamet

Dapagliflozin Xigduo

Empaglifloin Synjardy

Metformin + sulfonylurea Glipizide Metaglip and generic

Glyburide Glucovance and generic

Metformin + thiazolidinedione Pioglitazone Actoplus Met

Rosiglitazone Avandamet

Thiazolidinedione + DPP-4 inhibitorPioglitazone + alogliptin Oseni

Thiazolidinedione + sulfonylurea Pioglitazone + glimepiride Duetact

Rosiglitazone + glimepiride Avandaryl

Traditional Treatment of Diabetes

• By managing hyperglycemia/A1C targets

• By pathophysiology

Hyperglycemia

β α

Treatment based on pathophysiology

INSULIN

RESISTANCE

↓glucose reabsorption

↑insulin

Decreases Hepatic

glucose

production

increases

incretin effect

Improve

neurotransmitter

dysfunction

Increases glucose

uptake

DeFranzo R, et al. Diabetes Care, Volume 36, Supplement 2, August 2013 S127-138

Islet- α cell

decreases

glucagon

secretion

Lipolysis

decreased

DPP IV inhibitors

GLP-1 agonists

Sulfonylureas

Meglitinides

Insulin GLP-1 agonists

SGLT-2

inhibitors

TZDs

InsulinInsulin

TZDs

GLP-1 agonists

DPP IV inhibitors

Metformin

Cardiovascular Outcome Trials and New DM2 Medications

14

15

2008 FDA CV Safety of DM Drugs

• Primarily in response to findings of possible

increased CV risk with rosiglitazone

• FDA recommendation:

• “To establish safety of a new antidiabetic therapy to

treat Type 2 diabetes, sponsors should demonstrate

that the therapy will not result in an unacceptable

increase in cardiovascular risk.”

• The CV outcomes trials are characterized by:

– Inclusion of High-risk patients

– Non-inferiority design (show no harm compared to

placebo)

– If the non-inferiority threshold is met, these trials

can also assess for superiorityKaul. Diabetes Care July 1, 2017

16

Noninferiority and Superiority

Criteria in CVOTs

16

1.3

1.0

95%

Confidence

Interval

Noninferiority

• Upper bound of the confidence interval for the primary endpoint is less than a prespecified threshold (often 1.3, but criteria vary with study design)

• Means study drug performed no worse than comparator and is safe

Superiority

• Upper bound of confidence interval for the primary endpoint is typically less than 1 (criteria may vary with study design)

• Tested after noninferiority criteria are met

• Means study drug reduced CV outcomes relative to comparator

Agents Shown

to Have CV

Safety:All anti-

hyperglycemic

agents evaluated in

CVOTs to date

Agents Shown

to Reduce CV

Outcomes:Canagliflozin

Empagliflozin

Liraglutide

Semaglutide

17

Noninferiority and Superiority

Criteria in CVOTs

• Looking at major adverse CV events

(MACE)

1. CV death

2. Nonfatal MI

3. Nonfatal stroke

17

Cardiovascular Outcome Trials-- SGLT2 Inhibitors

Sodium Glucose Co-Transporter 2

SGLT2 Inhibitors Promote Urinary Glucose Excretion

• SGLT2 mediates most (≈ 90%) glucose reabsorption from the proximal renal tubular lumen back into the circulation

• SGLT2 inhibitors lower the threshold at which glucose is excreted, leading to

– Increased urinary glucose excretion

– Decreased return of glucose to circulation

– Decreased blood glucose levels

Chao E, Henry R. Nature Rev Drug Discov. 2010;9:551-559.

Bowman’s

capsule

Return

to

circulation

Urinary excretion

Glucose

SGLT2

Proximal

renal

tubule

Sodium-glucose co-transporter 2 inhibitors (SGLT2)

Benefits :

•Weight loss

•Improved systolic BP

•A1c reduction

Adverse effects

•Increase LDL

•Increase risk of yeast

infections

•Not recommended in

over 75 y/o

Canagliflozin

(Invokana 100 & 300 mg)

GFR>45 mL/min/1.73m²

Dapaglifozin

(Farxiga 5 & 10 mg QD) )

GFR>60

Empagliflozin

(Jardiance 10 & 25 mg)

GFR>45

EMPA-REG OUTCOME(EMPAGLIFLOZIN CARDIOVASCULAR OUTCOME

EVENT TRIAL IN TYPE 2 DIABETES MELLITUS

PATIENTS)

Clinical Outcomes with Antihyperglycemic Agents

22

EMPA-REG Trial

• First large, prospective, randomized, placebo-controlled

trial to report a CV benefit of antidiabetes drugs

• Study design: Multicenter, randomized, double-blind, placebo-controlled study

• Primary objective: To assess the effects of empagliflozin vs. placebo on CV morbidity and mortality in patients with T2DM who were at high risk for CV events and were receiving standard care

aHbA1c 7.0%-9.0% in patients who did not receive any glucose lowering agents ≥12 weeks prior to randomizationbPooled empagliflozin group

Zinman B et al. N Engl J Med 2015;373:2117-28

EMPA-REG OUTCOME:

Study Design and ObjectivesEligibility Criteria1:

• T2DM with HbA1c

7.0%-10.0%a

• Age ≥18 years

• BMI ≤45 kg/m2

• GFR ≥30 mL/min/

1.73 m2

• Had established

CV disease

Empagliflozin (10 mg or 25 mg QD) +

Standard Care

N=4687b

Placebo +

Standard Care

N=2333

R

1:1:1

Primary Outcome:

• Composite of CV death,

nonfatal MI, or nonfatal

stroke

Key Secondary Outcome


nonfatal MI, nonfatal

stroke, and

hospitalization for UA

Cumulative incidence functionaThe primary outcome was a composite of CV death, nonfatal MI, or nonfatal stroke (3-point MACE); bTwo-sided tests for

superiority were conducted (statistical significance was indicated if p≤.0498)

Data from Zinman B et al. N Engl J Med 2015;373:2117-28

EMPA-REG OUTCOME:

Primary Outcome (3-point MACE)a

No. at Risk:

Empagliflozin 4687 4580 4455 4328 3851 2821 2359 1534 370

Placebo 2333 2256 2194 2112 1875 1380 1161 741 166

14% RRR in primary

outcome

32% RRR in all-cause

mortality

38% RRR CV death

HR 0.86 (95.02% CI 0.74, 0.99); p=.04b20

15

10

5

0

Pa

tie

nts

Wit

h E

ve

nt

(%)

0 6 12 18 24 30 36 42 48Time (Months)

Placebo

Empagliflozin

Hazard ratio (95% CI) P value

Primary composite endpoint* 0.86 (0.74-0.99) 0.04

Secondary composite endpoint† 0.89 (0.78-1.01) 0.08

Death from any cause 0.68 (0.57-0.82) <0.001

CV death 0.62 (0.49-0.77) <0.001

Fatal or nonfatal MI 0.87 (0.70-1.09) 0.23

Hospitalization for HF 0.65 (0.50-0.85) 0.002

Hospitalization for HF or CV death 0.66 (0.55-0.79) <0.001

Clinical Outcomes with Empagliflozin

26

EMPA-REG OUTCOME Pooled Analysis

(N=7020)

*CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; †CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and

hospitalization for unstable angina.

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

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

0.00 0.50 1.00 1.50

Favors empagliflozin

Median follow-up: 3.1 years

Renal Outcomes with Empagliflozin Over

3.2 Years

27

EMPA-REG RENAL

(N=7020)

Arrows = relative risk reduction.

*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.

CI, confidence interval; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.

Wanner C, et al. N Engl J Med. 2016;375:323-334.

18.8

12.7

0

5

10

15

20

Incident or worsening nephropathy

Pa

tie

nts

(%

)

39%P<0.001

9.7

5.5

0

2

4

6

8

10

12

Post-hoc composite outcome*

Pa

tie

nts

(%

)

44%P<0.001

16.2

11.2

0

5

10

15

20

Progression to macroalbuminuria

Pa

tie

nts

(%

)

38%P<0.001

The label update makes

Empagliflozin (Jardiance) the

first-ever diabetes medication to

be approved for reducing heart-

related death.

CANVAS (CANAGLFLOZIN

CARDIOVASCULAR

ASSESSMENT STUDY)Clinical Outcomes with Antihyperglycemic Agents

29

• Made up of 2 studies: CANVAS and CANVAS-R

• Canagliflozin – FIRST APPROVED SGLT-2 inhibitor

• CANVAS studies began in 12/2009 – first approval FDA in 3/2013 with interim data from CANVAS

• Since had to unmask some CV outcomes data in regulatory filing for approval, didn’t expand original sample set

• So made CANVAS-R, a separate trial in 2014 with added assessment for albuminuria

• Integrated analysis for CV, kidney, and safety outcomes to maximize statistical power

• 10,142 participants in the combined studies with T2 DM and high CV risk

The CANVAS PROGRAM

• Study design: Multicenter, randomized, double-blind, placebo-controlled, parallel group study

• Primary objective: To determine the effects of canagliflozin compared to placebo (against a background of standard care) on the risk of CV disease and to provide data on safety and tolerability

1. Neal B et al. Am Heart J 2013;166(2):217-223.e112. Neal B et al. N Engl J Med 2017;Ahead of print

1. aIncreased CV risk defined as: Age ≥30 years with history of CV disease or age ≥50 years with ≥2 CV risk factors (≥10 years diabetes duration, systolic BP >140 mm Hg while receiving antihypertensive agent(s), current smoking, microalbuminuria or macroalbuminuria, or HDL-C <1 mmol/L [<38.7 mg/dL])2

CANVAS:

Study Design and Objectives1

Eligibility Criteria:

• T2DM with HbA1c

7.0%-10.5%

• Elevated risk for CV

diseasea

Canagliflozin (100 mg)

N=1445

Placebo

N=1441

R

1:1:1

Primary Outcome:



stroke



nonfatal MI, nonfatal

stroke, hospitalization

for UA

Canagliflozin (300 mg)

N=1441

• Study design: Multicenter, randomized, double-blind, placebo-controlled,

parallel group study

• Primary objective: To assess the effect of canagliflozin compared to placebo

on progression of albuminuria in participants with T2DM receiving standard

care but with inadequate glycemic control and at elevated risk of CV eventsaIncreased CV risk defined as: Age ≥30 years with history of CV disease or age ≥50 years with ≥2 CV risk factors (≥10 years diabetes duration, systolic BP >140 mm Hg while receiving antihypertensive agent(s), current smoking, microalbuminuria or macroalbuminuria, or HDL-C <1 mmol/L [<38.7 mg/dL])2

bDose may be increased to 300 mg once daily after first 13 weeks of treatment

1. https://clinicaltrials.gov/ct2/show/NCT019897542. Neal B et al. N Engl J Med 2017;Ahead of print

CANVAS-Renal:

Study Design and Objectives1


• T2DM with HbA1c

7.0%-10.5%

• Elevated risk for CV

diseasea

Canagliflozin (100 mg)b

Placebo

R

1:1

Primary Outcome:

• Progression of

albuminuria

Key Secondary Outcomes

• Regression of albuminuria

• Change in eGFR from

baseline to last off-

treatment measurement

• UACR at last

on-treatment visit

• MACE

aThe primary composite outcome in the time-to-event analysis was the first occurrence of CV death, nonfatal MI, or nonfatal stroke - “Big 3”The integrated CANVAS Program comprised two trials: CANVAS and CANVAS-RenalThe HRs and 95% CIs were estimated with the use of Cox regression models with stratification according to trial and history of CV disease for all canagliflozin groups combined vs. placebo

Data from Neal B et al. N Engl J Med 2017;Ahead of print

Integrated CANVAS Program:

Primary Outcomea

No. at risk

Placebo 4347 4153 2942 1240 1187 1120 789 216

Canagliflozin 5795 5566 4343 2555 2460 2363 1661 448

0

5

10

15

20

Pati

en

ts W

ith

Even

t (%

)

Time From Randomization (Weeks)

26 78 182 2860 388234130

HR: 0.86 (95% CI, 0.75-0.97)

p<.001 for noninferiority

p=.02 for superiority

52 104 208 312260156

Canagliflozin

Placebo

14% RRR for

MACE


Primary composite endpoint* 0.86 (0.75-0.97) 0.02†

CV death 0.87 (0.72-1.06)

Nonfatal MI 0.85 (0.69-1.05)

Nonfatal stroke 0.90 (0.71-1.15)

Fatal or nonfatal MI 0.89 (0.73-1.09)

Fatal or nonfatal stroke 0.87 (0.69-1.09)

HF hospitalization 0.67 (0.52-0.87)

CV death or HF hospitalization 0.78 (0.67-0.91)

All-cause death 0.87 (0.74-1.01)

Progression of albuminuria 0.73 (0.67-0.79)

40% reduction in eGFR, renal

replacement therapy, or renal death

0.60 (0.47-0.77)

Clinical Outcomes with Canagliflozin

34

CANVAS Program

(N=10,142)

*CV death, nonfatal MI, or nonfatal stroke. †Superiority.


Neal B, et al. N Engl J Med. 2017 Jun 12 [epub ahead of print].

0.00 0.50 1.00 1.50

Favors canagliflozin


But none of indiv

components

significantly reduced

* Empa-Reg had CV

death RRR 38%!!!

Canagliflozin and Amputation5/18/2016

CANVAS trial Interim analysis

• 7/1000 with Canagliflozin 100 mg

• 5/1000 Canagliflozin 300 mg

• 3/1000 with Placebo

• 71% amputations in toe or metatarsal

• Highest risk in patients with PVD or prior amputation

Mechanism unclear

Volume depletion?

Higher risk of Amputation with diuretic use

Summary

• Empagliflozin and canagliflozin reduce composite

endpoint of CV death, nonfatal MI or nonfatal stroke

compared to placebo in patients with high CV risk

• Empagliflozin reduces hospitalization for heart failure

• “Thrift substrate” hypothesis where in conditions of mild

hyperketonemia, B-hydroxybutyrate is preferentially

utilized by the heart in preference to fatty acids, resulting

in improved transduction of VO2 into myocardial efficiency.

SGTLT-2 inhibitors:

Reduction in Heart Failure Risk?

THE CVD-REAL STUDY

Landmark real-world evidence from an

international study of more than

300,000 patients with type-2 diabetes

Multinational, retrospective, observational cohort study in

patients with type 2 diabetes mellitus who are initiating

treatment with a sodium-glucose co-transporter-2 (SGLT-2)

inhibitor or another glucose-lowering drug. CVD-REAL data are presented at the American College of Cardiology 66th

Annual Scientific Session

Aim

• CVD-REAL is a comparative effectiveness study that aims

to compare new users of SGLT-2 inhibitors with new users

of other glucose-lowering drugs with regard to

hospitalization for heart failure and all-cause mortality.

The study analysis is based on data from at least six

countries: United States, United Kingdom, Germany,

Sweden, Denmark and Norway.

Design

1. CVD-REAL is a multinational, retrospective, non-

interventional, observational study spanning six

countries across two continents (North America and

Europe)

2. The study will include data from approximately 1.4

million patients from the time they start treatment with

an SGLT-2 inhibitor or other glucose-lowering drug to

the end of the follow-up period.

3. Depending on the launch date of the first SGLT-2

inhibitor in each participating country, this equates to a

period of 4–5 years.

Inclusion criteria

• Type 2 diabetes mellitus (diagnosed on or before the

index date)

• Aged 18 years or older on the index date

• New user receiving or dispensed a prescription of oral or

injectable SGLT-2 inhibitor medication or other glucose-

lowering drug, including fixed-dose combination products

containing these medication groups

• More than 1 year of data reported in the database before

the index date

Outcome measures• Primary outcome measures

Incidence of hospitalization for heart failure (from

index date to 1 year) based on the hospitalization

information obtained from general practice or hospital

records, electronic health records or national health

registers

• Secondary outcome measures

Incidence of all-cause mortality (from index date to 1

year) based on the information obtained from national

health registers

• Exploratory outcome measures

Estimate the incidence of acute myocardial infarction

and atrial fibrillation in both treatment groups

Data Collection

• The hospitalizations for heart failure analysis was conducted using deidentified patient data from Denmark, Germany, Norway, Sweden, United Kingdom and the United States

• Of the data reviewed, 41.8% of patients were on Farxiga (dapagliflozin), 52.7% on canagliflozin and 5.5% on empagliflozin

• The analysis of death from any cause was conducted patient data from Denmark, Norway, Sweden, United Kingdom and the United States

• Of the data reviewed, 51.0% of patients were on Farxiga (dapagliflozin), 42.3% on canagliflozin and 6.7% on empagliflozin.

Results

Compared with new users of other

glucose-lowering drugs users, new users of SGLT-

2 inhibitors had:

• Reduction in the the rate of hospitalization for

heart failure by 39% (p<0.001)

• Reduction in death from any cause by 51%

(p<0.001), compared to other T2D medicines

• For the composite endpoint of hospitalization for

heart failure and death from any cause, the

reduction was 46% (p<0.001).1

GLP-1 Receptor Agonists

Gastroenterology 2007 132, 2131-2157DOI: (10.1053/j.gastro.2007.03.054

Antidiabetic Activities of GLP-1

• Incretin peptide hormone

• Secreted from the distal small intestine L-cells in response to oral food intake

48

GLP-1 Receptor Agonists

FDA-Approved Agents

• Albiglutide

• Dulaglutide

• Exenatide

• Exenatide ER

• Liraglutide

• Semaglutide

Key Features

• Injectable administration

• Mimic action of native

GLP-1


dependent insulin

secretion

• Suppress glucagon

production


ER, extended release; GLP-1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

LEADER(LIRAGLUTIDE EFFECT AND ACTION IN DIABETES:

EVALUATION OF CARDIOVASCULAR OUTCOME

RESULTS)


49

• Study design: International, randomized, placebo-controlled study

• Primary objective: To evaluate the effect of liraglutide compared to placebo

on the incidence of CV events in adults with type 2 diabetes

aCoronary heart disease, cerebrovascular disease, peripheral vascular disease, CKD stage ≥3, chronic heart failure NYHA class II/IIIbMicroalbumiuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle-brachial index (the ratio of the systolic BP at the ankle to the systolic BP in the arm) of <0.9cLiraglutide was administered at 0.6 mg daily for 1 week, 1.2 mg/day for an additional week, and a potential maximum dosage of 1.8 mg/day thereafter

Marso SP et al. Am Heart J 2013;166:823-30.e5

LEADER:

Study Design and Objectives


• T2DM with

HbA1c ≥7.0%

• Age ≥50 years with

≥1 coexisting CV

conditiona or

• Age ≥60 years with

≥1 CV risk factorb

Liraglutide (0.6-1.8 mg)c +

Standard Care

N=4668

Placebo +

Standard Care

N=4672

R

1:1

Primary Outcomes:



stroke



nonfatal MI, nonfatal stroke,

revascularization,

hospitalization for UA, or

heart failure

aThe primary composite outcome in the time-to-event analysis was the first occurrence of CV death, nonfatal MI, or nonfatal strokeThe cumulative incidences were estimated with the use of the Kaplan-Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression modelThe data analyses were truncated at 54 months, because <10% of the patients had an observation time beyond 54 months

Data from Marso SP et al. N Engl J Med 2016;375:311-22

LEADER: Primary Outcomea

CV Death, Nonfatal MI, or Nonfatal Stroke

No. at risk

Liraglutide 4668 4593 4496 4400 4280 4172 4072 3982 1562 424

Placebo 4672 4588 4473 4352 4237 4123 4010 3914 1543 407

13% RRR CV Events

NNT=66 to prevent 1

primary outcome over

36m

0

5

10

15

20

Pati

en

ts W

ith

Even

t (%

)

Time From Randomization (Months)

6 12 24 36 480 423018 54

HR: 0.87 (95% CI, 0.78-0.97)

p<.001 for noninferiority

p=.01 for superiority

Liraglutide

Placebo

The cumulative incidences were estimated with the use of the Kaplan-Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression modelThe data analyses were truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months

Data from Marso SP et al. N Engl J Med 2016;375:311-22

LEADER: CV DeathTime-to-Event Analysis

Time From Randomization (Months)

No. at risk

Liraglutide 4668 4641 4599 4558 4505 4445 4382 4322 1723 484

Placebo 4672 4648 4601 4546 4479 4407 4338 4267 1709 465

0

2

4

6

8

Pati

en

ts W

ith

Even

t (%

)

6 12 24 36 480 423018 54

HR: 0.78 (95% CI, 0.66-0.93)

p=.007

Liraglutide

Placebo

22% RRR

NNT= 98



Expanded composite endpoint† 0.88 (0.81-0.96) 0.005

Death from any cause 0.85 (0.74-0.97) 0.02

CV death 0.78 (0.66-0.93) 0.007


Nephropathy 0.78 (0.67-0.92) 0.003

Clinical Outcomes with Liraglutide

53

LEADER

(N=9340)

*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary

revascularization, and hospitalization for unstable angina or HF.

CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.

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

0.00 0.50 1.00 1.50

Favors liraglutide


• US Food and Drug Administration (FDA) has approved

Victoza® (liraglutide) injection 1.2 mg or 1.8 mg to reduce

the risk of major adverse cardiovascular events

(cardiovascular death, non-fatal myocardial infarction, or

non-fatal stroke) in adults with type 2 diabetes mellitus

and established cardiovascular disease

FDA Approval of New Indication with

LEADER Data

SUSTAIN 6(TRIAL TO EVALUATE CARDIOVASCULAR AND OTHER

LONG-TERM OUTCOMES WITH SEMAGLUTIDE IN

SUBJECTS WITH TYPE 2 DIABETES)


55

Clinical Outcomes with Semaglutide• N=3297 patients with T2D with CVD, CHF, CKD, or age ≥60

with ≥1 CV risk factor

• Randomization

• Semaglutide: n=1648

• Placebo: n=1649

• Noninferiority study: prespecified margin <1.8 for upper bound of 95% CI of the HR for the primary endpoint

• Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke

• Key secondary endpoints

• Composite of CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF

• Composite of all-cause death, nonfatal MI, nonfatal stroke

• Retinopathy complications

• New or worsening nephropathy

56

SUSTAIN 6 Study Design

CI, confidence interval; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; HF,

heart failure; HR, hazard ratio; MI, myocardial infarction; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with

Semaglutide in Subjects with Type 2 Diabetes.




Expanded composite endpoint† 0.74 (0.62-0.89) 0.002

All-cause death, nonfatal MI, nonfatal stroke 0.77 (0.61-0.97) 0.03

Death from any cause 1.05 (0.74-1.50) 0.79 (NS)

CV death 0.98 (0.65-1.48) 0.92 (NS)

Nonfatal MI 0.74 (0.51-1.08) 0.12 (NS)

Nonfatal stroke 0.61 (0.38-0.99) 0.04

Revascularization 0.65 (0.50-0.86) 0.003

Retinopathy complications 1.76 (1.11-2.78) 0.02

New or worsening nephropathy 0.64 (0.46-0.88) 0.005

Clinical Outcomes with Semaglutide

57

SUSTAIN 6 Results

(N=3297)

*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization,

and hospitalization for unstable angina or HF.

CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction.


0.00 1.00 2.00 3.00

Favors semaglutide


26% RRR the Big 3

NNT is 45 to prevent one

primary outcome over 24

months

ELIXA

(EVALUATION OF

LIXISENATIDE IN ACUTE

CORONARY SYNDROME)Clinical Outcomes with Antihyperglycemic Agents

58

Clinical Outcomes with Lixisenatide

Study Design

• N=6068 patients with T2D and MI or unstable angina within 180 days prior to enrollment

• Randomization• Lixisenatide: n=3034

• Placebo: n=3034

• Noninferiority criteria: upper bound of 95% CI of the HR for the primary endpoint <1.3

• Primary endpoint: composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina

• Key secondary endpoints• Composite of CV death, nonfatal MI, nonfatal

stroke, or hospitalization for unstable angina or HF

• Composite of CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina or HF, or coronary revascularization

Key Results

• Median follow-up: 25 months

• Difference from placebo at 25 weeks• A1C: −0.27% (95% CI −0.31 to −0.22;

P<0.001)

• Weight: −0.7 kg (95% CI, −0.9 to −0.5 kg; P<0.001)

• SBP: −0.8 mm Hg (95% CI, −1.3 to −0.3 mm Hg)

• CV outcomes• Primary: HR 1.02 (95% CI 0.89 to 1.17);

P<0.001 for noninferiority; P=0.81 for superiority

• Increased rates of gastrointestinal events in lixisenatide-treated patients

• Rates of serious adverse events, severe hypoglycemia, pancreatitis, pancreatic neoplasms similar to placebo

59

ELIXA Study Design


Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257.

Clinical Outcomes with Lixisenatide

60

ELIXA

(Patients with T2D and CVD; N=6068)

*CV death, nonfatal MI, or nonfatal stroke, and hospitalization for unstable angina; †CV death, nonfatal MI, nonfatal stroke, hospitalization for

unstable angina, hospitalization for HF, and coronary revascularization.


Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257.

0.00 1.00 2.00 3.00




CV death 0.98 (0.78-1.22) 0.85


Stroke 1.12 (0.79-1.58) 0.54

Unstable angina 1.11 (0.47-2.62) 0.81

Hospitalization for heart failure 0.96 (0.75-1.23) 0.75


Favors lixisenatide

All NS

EXSCEL(EXENATIDE STUDY OF CARDIOVASCULAR EVENT

LOWERING)


61

Clinical Outcomes with Exenatide

Study Design

• N=14,752 patients with T2D with or without CVD

• By design, ≥70% had CVD (n=10,782; 73.1%)

• Randomization• Exenatide: n=7356

• Placebo: n=7396

• Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the primary endpoint HR

• Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke

• Secondary endpoints: all-cause death, CV death, nonfatal or fatal MI, nonfatal or fatal stroke, and hospitalization for acute coronary syndrome or HF

Key Results

• Median follow-up: 3.2 years

• Difference from placebo at trial end• A1C: −0.53% (95% CI, −0.57% to −0.50%;

P<0.001)

• Weight: −1.3 kg (95% CI, −1.4 to −1.1 kg; P<0.001)

• SBP: −1.6 mm Hg (95% CI, −1.9 to −1.2 mm Hg; P<0.001)

• CV outcomes• Primary endpoint: HR 0.91 (95% CI 0.83 to

1.00); P<0.001 for noninferiority, P=0.06 for superiority

• No difference between treatment groups in confirmed cases of pancreatitis, pancreatic cancer, or medullary thyroid carcinoma

• More cases of thyroid papillary carcinoma in exenatide (n=10) than placebo group (n=4)

62

EXSCEL

CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; HR, hazard ratio;

MI, myocardial infarction.

Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print].

Hazard ratio (95% CI) P value†


Death from any cause 0.86 (0.77-0.97) NS

CV death 0.88 (0.76-1.02)

Fatal or nonfatal MI 0.97 (0.85-1.10)

Fatal MI 1.29 (0.63-2.66)

Fatal or nonfatal stroke 0.85 (0.70-1.03)

Fatal stroke 0.71 (0.39-1.30)

Hospitalization for HF 0.94 (0.78-1.13)

Hospitalization for ACS 1.05 (0.94-1.18)

Clinical Outcomes with Exenatide

63

EXSCEL

(N=14,752)

*CV death, nonfatal MI, or nonfatal stroke. †For superiority.

ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering;

HF, heart failure; MI, myocardial infarction; NS, not statistically significant based on hierarchical testing plan.

Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print].

0.00 1.00 2.00 3.00

Favors exenatide


Conclusions

• Semaglutide and liraglutide with decrease in MACE

• Animal studies have indicated that GLP-1 receptor

activation in heart tissue may have benefits including

improved LV function and protection from ischemic

reperfusion injury

DPP4 Inhibitors

66

DPP-4 Inhibitors

FDA-Approved Agents

• Alogliptin

• Linagliptin

• Saxagliptin

• Sitagliptin

Key Features

• Oral administration

• Inhibit actions of DPP-4

• Increase endogenous

GLP-1 and GIP levels


dependent insulin

secretion

• Suppress glucagon

production

DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

TECOS

(TRIAL EVALUATING CARDIOVASCULAR

OUTCOMES WITH SITAGLIPTIN)


67

Clinical Outcomes with Sitagliptin

Study Design

• N=14,671 patients with T2D and CVD

• Randomization

• Sitagliptin: n=7332 (6972 completed)

• Placebo: n=7339 (6905 completed)

• Noninferiority study: 1.3 marginal upper

boundary of 2-sided 95% CI

• Primary composite outcome:

cardiovascular death, nonfatal myocardial

infarction, nonfatal stroke, or

hospitalization for unstable angina

• Secondary composite outcome:

cardiovascular death, nonfatal myocardial

infarction, or nonfatal stroke.

Key Results


• Least squares mean difference in A1C:

-0.29% (95% CI -0.32 to -0.27) for

sitagliptin vs placebo

• Noninferior to placebo for

cardiovascular outcomes

• Primary HR: 0.98 (0.88-1.09); P<0.001

• Secondary HR: 0.99 (0.89-1.11); P<0.001

• No difference between sitagliptin and

placebo in incidence of infections,

cancer, renal failure, hypoglycemia, or

noncardiovascular death

68

TECOS

CI, confidence interval; HR, hazard ratio; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.

Green JB, et al. N Engl J Med. 2015;373:232-242.

Primary and Secondary Outcomes with

Sitagliptin

69

TECOS Per Protocol Analysis

(n=14,523)

*Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.

†Secondary composite: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

NF, noninferiority; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.



Primary composite endpoint* 0.98 (0.88-1.09) <0.001 (NF)

Secondary composite endpoint† 0.99 (0.89-1.11) <0.001 (NF)

Acute pancreatitis 1.80 (0.86-3.76) 0.12

Any cancer (except

nonmelanoma skin cancer)0.93 (0.78-1.10) 0.38

Pancreatic cancer 0.91 (0.37-2.25) 0.85

Severe hypoglycemia 1.13 (0.89-1.44) 0.31

Favors sitagliptin

0.00 1.00 2.00 3.00 4.00



CV death 1.03 (0.89-1.19) 0.71

Hospitalization for unstable angina 0.90 (0.70-1.16) 0.42


Fatal or nonfatal stroke 0.97 (0.79-1.19) 0.76



Hospitalization for heart failure or CV death 1.02 (0.90-1.15) 0.74

Individual Secondary Outcomes with

Sitagliptin

70

0.50 1.00 1.50

TECOS Intent to Treat Analysis

(n=14,671)

CV, cardiovascular; MI, myocardial infarction; NF, noninferiority; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.


Favors sitagliptin


EXAMINE(EXAMINATION OF CARDIOVASCULAR OUTCOMES

WITH ALOGLIPTIN VERSUS STANDARD OF CARE)


71

Clinical Outcomes with Alogliptin

Study Design• N=5380 patients with T2D and

ACS

• Randomization

• Alogliptin: n=2701

• Placebo: n=2679

• Noninferiority study: prespecified HR margin = 1.3 for primary endpoint

• Primary composite endpoint: CV death, nonfatal MI, or nonfatal stroke

• Secondary: CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina

Key Results

• Median follow-up: 18 months

• Least squares mean difference in A1C:

-0.36% (95% CI -0.43 to -0.28;

P<0.001) for alogliptin vs placebo

• CV outcomes

• Primary HR: 0.96 (≤1.16); P=0.32

• Secondary HR: 0.95 (≤1.14*); P=0.26

• No difference between alogliptin and

placebo in incidence of acute and

chronic pancreatitis, cancer, renal

impairment, angioedema, or severe

hypoglycemia

72

EXAMINE

*Upper boundary of 1-sided repeated CI, alpha level 0.01.

CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care;

HR, hazard ratio; MI, myocardial infarction.

White W, et al. N Engl J Med. 2013;369:1327-1335.


Primary composite 0.96 (≤1.16)* 0.32

Primary endpoint components

CV death 0.79 (0.6-1.04) 0.10

Nonfatal MI 1.08 (0.88-1.33) 0.47

Nonfatal stroke 0.91 (0.55-1.50) 0.71

Primary secondary endpoint† 0.95 (≤1.14)* 0.26



73

0.00 1.00 2.00

EXAMINE Safety Endpoints

(n=5380)


†CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina.



White W, et al. N Engl J Med. 2013;369:1327-1335.

Favors alogliptin

Median follow-up: 18 months


74

EXAMINE Safety Endpoints

(n=5380)


†CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina.



Zannad. The Lancet. Vol 385. May 23, 2015

Median follow-up: 18 months

SAVOR-TIMI(SAXAGLIPTIN ASSESSMENT OF VASCULAR OUTCOMES

RECORDED IN PATIENTS WITH DIABETES MELLITUS–

THROMBOLYSIS IN MYOCARDIAL INFARCTION)


75

Clinical Outcomes with Saxagliptin

Study Design

• N=16,492 patients with T2D and CVD

or CVD risk

• Randomization

• Saxagliptin: n=8280

• Placebo: n=8212

• Superiority study with provision to test

for noninferiority

• Primary composite endpoint: CV death,

nonfatal MI, or nonfatal ischemic stroke

• Secondary: CV death, nonfatal MI,

nonfatal ischemic stroke, hospitalization

for HF, coronary revascularization, or

unstable angina

Key Results


• Endpoint A1C

• Saxagliptin: 7.7% ± 1.4% (P<0.001 vs placebo)

• Placebo: 7.9% ± 1.5%

• CV outcomes

• Primary HR: 1.00 (0.89-1.27); P=0.99

• Secondary HR: 1.02 (0.94-1.11); P=0.66

• Higher incidence of HF hospitalization in

saxagliptin group

• No difference between groups in incidence of

acute or chronic pancreatitis; fewer cases of

pancreatic cancer in saxagliptin group; more

cases of nonfatal angioedema in saxagliptin

group (8 vs 1)

76

SAVOR-TIMI

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin

Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.

Scirica BM, et al. N Engl J Med. 2013;369,1317-1326.

Clinical Outcomes with Saxagliptin

77

SAVOR-TIMI Prespecified Composite Endpoints and Mortality

(n=16,492)





CV death 1.03 (0.87-1.22) 0.72

*CV death, nonfatal MI, or nonfatal ischemic stroke; †CV death, nonfatal MI, nonfatal ischemic stroke, hospitalization for HF, coronary

revascularization, or unstable angina.

CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular

Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.


Favors saxagliptin

0.50 1.00 1.50


Individual Secondary Outcomes with

Saxagliptin

78

*Doubling of creatinine, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL

CI, confidence interval; CV, cardiovascular; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes

Mellitus–Thrombolysis in Myocardial Infarction.


SAVOR-TIMI Prespecified Individual Endpoints

(n=16,492)

Favors saxagliptin


Myocardial infarction 0.95 (0.80-1.12) 0.52

Ischemic stroke 1.11 (0.88-1.39) 0.38

Hospitalization for unstable angina 1.19 (0.89-1.60) 0.24


Hospitalization for coronary revascularization 0.91 (0.80-1.04) 0.18

Renal endpoint* 1.08 (0.88-1.32) 0.46

Hospitalization for hypoglycemia 1.22 (0.82-1.83) 0.33

0.00 1.00 2.00


How about Heart Failure Risk?

Conclusion: DPP4-Inhibitors

• No significant relative reduction in major cardiovascular

events in all DPP4 Inhibitors

• Possible increase in heart failure in patient with type 2

diabetes with saxagliptin and alogliptin

Summary: DM Contemporary Care

• Identify individual treatment goals

• Food for thought. Treatment should not be based on traditional

methodology on A1C or glucose levels solely but also taking into

consideration the individual’s CV risk factors.

▪ GLP1ra and SGLT2i as first options with metformin based on safety efficacy

in reducing glucose and positive effect on CV risk parameters especially

weight and blood pressure

• Institute personalized comprehensive care for people with diabetes

▪ Start intensive lifestyle modification for glycemic control while

concomitantly starting medications

▪ Choose medications based on safety, efficacy and characteristics

▪ Monitor every three months intensify/advance treatment as needed

83

Summary: Cardiovascular Outcome trials

▪Agents that significantly decreased MACE

•Empagliflozin

•Canagliflozin

•Semaglutide

•Liraglutide

▪Secondary endpoint of all cause death was significantly

reduced in EMPA-REG and LEADER

▪Hospitalization for heart failure was reduced only in EMPA-

REG

▪Heart failure may be increased in aloglitin and saxagliptin

84

Case 1:

• A 55 year old male with a past medical history of coronary

artery disease status post stent placement and 5 year

history of diabetes presents to your clinic. A1C is 8.2%.

Left ventricular ejection fraction is within normal limits.

Creatinine is 1.1 with eGFR 68.

He is currently on metformin therapy

What would be the next best agent to add on?



• C. sitagliptin


Case 2:

• A 63 year old female with PMH of CVA and10 year history

of diabetes presents to your clinic. A1C is 7.8%. LVEF is

28%. On PE, lungs are clear to auscultation and there is

no evidence of edema/volume overload. Creatinine is 0.9

with eGFR 72.

What would be the agents that you would you avoid?



• C. sitagliptin


THANK YOU

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