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Keith Miller, MD, PhD

Bryan Heart Fall Conference

September 2, 2017

Cardiovascular Outcomes Cardiovascular Outcomes Cardiovascular Outcomes Cardiovascular Outcomes

Trials Trials Trials Trials in Type II Diabetes:in Type II Diabetes:in Type II Diabetes:in Type II Diabetes:SGLTSGLTSGLTSGLT----2 Inhibitors and 2 Inhibitors and 2 Inhibitors and 2 Inhibitors and

GLPGLPGLPGLP----1 Receptor Agonists1 Receptor Agonists1 Receptor Agonists1 Receptor Agonists

Managing Cardiovascular Risk in the

Diabetic Patient

• Until recently, T2D therapies other than metformin had little obvious favorable effect on CV

outcomes

• Most cardiologists have focused their efforts on managing traditional risk factors (hypertension,

hyperlipidemia, overweight/obesity)

• Occasionally stop drugs that may cause HF (e.g., glitazones)

• Results from recent FDA-mandated cardiovascular outcomes trials (CVOTs) have shown not only

CV safety, but also reduced CV and all-cause mortality, and hospitalization for heart failure

• These trials include patients who are common in cardiologists’ practices

• Magnitude of beneficial results compares favorably with the landmark cardiology trials that have

shaped our current standards of care in primary and secondary prevention of CV events (statin

trials, BP lowering trials, etc.)

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Summary of Glycemic Control Trials

Intensive vs. Less-Intensive Glycemic Control

Macrovascular Mortality

On Study Long-Term On Study Long-Term

ACCORD ⇔ N/A ⇑ N/A

ADVANCE ⇔ N/A ⇔ N/A

UKPDS ⇔ ⇓ ⇔ ⇓

VADT ⇔ N/A ⇔ N/A

Bergenstal RM et al. Am J Med. 2010;123(4):374.e9-18.

• Significant improvements in

microvascular outcomes

• Disappointing results in

cardiovascular (macrovascular)

outcomes

Residual CV Risk in Recent Diabetes Trials

PLACEBO 10 year EVENT RATES (%)

CV Death, MI,

Stroke Death CV death MI Stroke

EMPA-REG 43.9 28.6 20.2 19.3 10.5

CANVAS 31.5 19.5 12.8 12.6 9.6

SUSTAIN-6 44.4 18.2 12.9 14.0 8.0

LEADER 39 25 16 19 11

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Diabetes Drugs:CVD or Mortality Risk Benefits

• Biguanides (metformin)– Few randomized, but many observational studies available

– Reduces risk of MI by 39%, mortality by 36% (UKPDS)– First choice in T2DM patients with and without atherosclerotic vascular disease

• Sulfonylureas– ”black box” CV warning from the FDA regarding heightened risk for CV events

– Reduction of microvascular complications

• Thiazolidinediones (TZDs)– Heightened HF risk, as well as weight gain and potential fracture risk

• Dipeptidyl peptidase-4 inhibitors– Neutral CVOT results so far; questions about incident HF risk

• Insulin– No demonstrated CV benefit

Summary of Key Findings of the 4 Positive CVOTs in T2DM

EMPA-REG OUTCOME CANVAS and CANVAS-R LEADER SUSTAIN-6

Agent Empagliflozin (Jardiance®) (SGLT2 inhibitor)

Canagliflozin (Invokana®)

(SGLT2 inhibitor)

Liraglutide (Victoza®)

(once-daily GLP-1 agonist)

Semaglutide (Farxiga®) (once-weekly GLP-1 agonist)

Inclusion criteria All with T2D and CVD

HbA1c 7%-10%

Age >30 yrs with CVD or >50

yrs with ≥2 CV risk factorsHbA1c 7%-10%

Age >50 yrs with CVD or >60

yrs with ≥1 CV risk factorHbA1c>7%

Age >50 yrs with CVD or >60

yrs with ≥1CV risk factorHbA1c>7%

Duration of trial 3.1 yrs 3.6 yrs 3.8 yrs 2.05 yrs

Baseline HbA1c 8.1% 8.2% 8.7% 8.7%

Primary endpoint1 ↓14% (1% to 26%) ↓14% (3% to 25%) ↓13% (2% to 22%) ↓26% (5% to 42%)

CV death ↓38% (23% to 51%) ↓13% (-6% to 28%) ↓22% (7% to 34%) ↓2% (-48% to 35%)

MI ↓13% (-9% to 30%) ↓15% (-5% to 31%) ↓12% (-3% to 25%) ↓26% (-8% to 49%)

Stroke ↑24% (-8% to 67%) ↓10% (-15% to 29%) ↓11% (-11% to 28%) ↓39% (1% to 72%)

HF hospitalization ↓35% (15% to 50%) ↓33% (13% to 48%) ↓13% (-5% to 27%) ↑11% (-23% to 61%)

Noteworthy adverse effects Genitourinary infections, no

excess DKA

Genitourinary infections,

Increased amputations

More gallstones, GI side

effects

Higher retinopathy rates

Likely broad mechanisms of

benefit

Rapid effects suggest a

hemodynamic or metabolic benefit, although a vascular

benefit may also occur

Lower overall event rates may

have attenuated outcomes benefits compared with

EMPA-REG

Slower effects suggest

benefits via less atherothrombosis and/or

avoidance of hypoglycemia

Slower effects suggest

benefits via less atherothrombosis

1Primary endpoint = 3-point MACE (death from CV causes, nonfatal MI, nonfatal stroke)

Summary of Positive CV Outcome Trials of Type 2 Diabetes Therapies Since 2008

Class Trial Name InclusionPRIMARY

ENDPOINT

SGLT2 Inhibitor EMPA-REG

CVD

HbA1c 7.0-10.0%

N=7,020

Empagliflozin 3.1 year median

follow-up3-Point MACE

Placebo

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SGLT2 Inhibition Reduces Renal Glucose Reabsorption

70-80 g/day

(280-320 Kcal/day)

• Study medication was given in addition to standard of care

• Primary outcome: 3-point MACE (CV death, nonfatal MI, nonfatal stroke)

• Analysis: Placebo vs. pooled empagliflozin groups

• Key inclusion criteria:• Adults with type 2 diabetes and established CVD

• BMI≤45 kg/m2; HbA1c 7-10%; eGFR≥30 mL/min/1.73m2

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

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EMPA-REG Key Results

Zinman B et al.

NEJM 2015;373:2117

• 14% RRR in 3-point MACE (p=0.04 for superiority)

• 1.6% ARR (NNT 62.5)• 38% RRR in CV death (p

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Incident or Worsening Nephropathy in EMPA-REG OUTCOME

N Engl J Med. 2016;375:323-334

• Statistically significant 39% reduction in

relative risk of incident or worsening

nephropathy vs placebo (p

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CANVAS Study: Canagliflozin (Invokana®)

• 1:1:1 canagliflozin 300 mg; canagliflozin 100 mg; placebo, in addition to best

practice management of T2D

• 10,142 participants

• Mean follow up 188.2 weeks

• Key Inclusion Criteria:

– CV disease

– or

– ≥50 years old with two or more CV risk factors

☟0.58%

☟1.6 kg

☟3.93 mmHg

☟1.39 mmHg

CV Outcomes in the Integrated CANVAS Program

• 14% RRR in 3-point MACE (p=0.02 for

superiority)

• Reductions in CV death, all-cause death,

heart failure hospitalization all in the right

direction, not statistically significant

• Favorable effects on renal outcomes (not

considered statistically significant)

• Adverse Events:

• Almost 2-fold increased amputation

risk in canagliflozin vs. placebo arms

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CV Outcomes in EMPA-REG versus CANVASSimilar Direction, Less In Magnitude in CANVAS

• All patients in EMPA-REG had established CV disease by enrollment criteria;

66% of CANVAS patients had established CV disease

Event Rates in Placebo Arm/1,000 patient-years

Trial 3-point MACE CV Death HF Hospitalization

EMPA-REG 43.9 20.2 14.5

CANVAS/R 31.5 12.8 8.7

SGLT-2 Inhbitor CV Outcome Trials

Drug Manufactuer CV Outcome Trial N Completed

Empagliflozin

(Jardiance®)

Boehringer

Ingelheim and Lilly Diabetes

EMPA-REG (published NEJM September 17,

2015)7,020 ✓

Canagliflozin

(Invokana®)

Janssen

Pharmaceuticals

CANVAS and CANVAS-R (published NEJM June

12, 2017)10,142 ✓

Dapagliflozin

(Farxiga®)AstraZeneca DECLARE-TIMI 58 (est. completion 2019) 17,150 2019

Summary of Positive CV Outcome Trials of Type 2 Diabetes Therapies Since 2008

Class Trial Name InclusionPRIMARY

ENDPOINT

SGLT2 Inhibitor EMPA-REG

CVD

HbA1c 7.0-10.0%

N=7,020

Empagliflozin 3.1 year median

follow-up3-Point MACE

Placebo

SGLT2 InhibitorCANVAS AND

CANVAS-R

CVD or Age≥50 and 2 or

more CV risk factors

N=10,142

Canagliflozin3.6 year mean

follow-up3-Point MACE

Placebo

GLP-1 Analog LEADER

CVD or CV RFs

HbA1c ≥7.0%

N=9,340

Liraglutide 3.8 year

median

follow-up3-Point MACE

Placebo

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Incretins and Diabetes Mellitus:Glucagon-like peptide-1 (GLP-1)

• Gut-derived member of the glucagon superfamily

• Released by small intestine in response to nutrient ingestion (glucose and fat)

• Amplify insulin secretory response to nutrients through receptors in the

pancreatic beta cell

• Account for 50-70% of total insulin secreted following an oral glucose load and contribute to the control of postprandial hyperglycemia

• Pharmacologic doses of GLP-1 promote weight loss through decreased gastric

emptying and appetite suppression centrally

Waldrop, et al. JACC 2016;67:1488-96

LEADER Design and Outcomes

Marso, et al. N Engl J Med 2016;375:311-22.

• 9,340 patients randomized

• Inclusion:

• HbA1c≥7%

• Age≥50 with CVD or age ≥60 plus ≥1 CV risk factor

• Treatment: 1.8 mg liraglutide daily or matching placebo

subcutaneously, in addition to standard of care

• Glycemic control: Mean difference HbA1c -0.40 %

• CV risk factors:

• 2.3 kg greater weight loss in liraglutide group

• BP difference 1.2/0.6 mmHg (liraglutide lower)

• Increased HR 3 bpm (liraglutide higher)

• CV outcomes:

• RRR 13% for 3-point MACE, significant for superioriority

(NNT 66 to prevent 1 event, 3 yrs)

• Significant reductions in CV death, death from any cause

(NNT 98)

• Non-significant reductions in nonfatal MI, nonfatal

stroke, hospitalization for heart failure

• Lower incidence of renal events in liraglutide group

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LEADER Adverse Events

• AE leading to permanent discontinuation of drug significantly greater in

liraglutide group (9.5% vs 7.3%, p

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SUSTAIN-6 Outcomes• Glycemic control: HbA1c difference -0.7% (0.5 mg

group); -1.0% (1 mg group)• CV risk factors:

• Body weight:

• -2.9 kg (0.5 mg group)

• -4.3 kg (1 mg group)

• SBP: 1.3-2.6 mmHg lower in semaglutide group

• Pulse: 2.1 to 2.4 bpm increase in semaglutide group

• CV outcomes

• RRR 26% for 3-point MACE, significant for

superiority (NNT 45 to prevent 1 event in 24

months)

• Driven by significant (39%) decrease in

nonfatal stroke and non-significant

(26%) decrease in nonfatal MI• Similar risk reductions both doses

• Nonsignificant reduction in death from CV

causes

SUSTAIN-6 Adverse Events• AE leading to permanent discontinuation of drug more common in semaglutide

group than placebo group (11.5/14.5% vs 5.7/7.6%)

– Mostly driven by gastrointestinal side effects

• Frequency of serious adverse events lower in semaglutide group

• Increased incidence of diabetic retinopathy in semaglutide roup (3.0% vs 1.8 %;

p=0.02)

– Most affected patients had retinopathy at baseline (83%)

• Fewer cases of new or worsening nephropathy in semaglutide group (3.8% vs

6.1%; p=0.005)

LEADER and SUSTAIN-6 Trials of GLP-1 agonists: liraglutide and semaglutide

• Time to benefit emerged later in the GLP-1 agonist trials compared with the

early benefit in EMPA-REG

• Suggests GLP-1 agonist benefits could be due to modified progression of

atherosclerotic vascular disease, rather than more acute hemodynamic effects

• Greater effect in SUSTAIN-6 on atherosclerotic endpoints (MI, stroke) supports an effect of GLP-1 agonists on atherosclerotic progression

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Summary of Key Findings of the 4 Positive CVOTs in T2DM

EMPA-REG OUTCOME CANVAS and CANVAS-R LEADER SUSTAIN-6

Agent Empagliflozin (Jardiance®) (SGLT2 inhibitor)

Canagliflozin (Invokana®)

(SGLT2 inhibitor)

Liraglutide (Victoza®)

(once-daily GLP-1 agonist)

Semaglutide (Farxiga®) (once-weekly GLP-1 agonist)

Inclusion criteria All with T2D and CVD

HbA1c 7%-10%

Age >30 yrs with CVD or >50

yrs with ≥2 CV risk factorsHbA1c 7%-10%

Age >50 yrs with CVD or >60

yrs with ≥1 CV risk factorHbA1c>7%

Age >50 yrs with CVD or >60

yrs with ≥1CV risk factorHbA1c>7%

Duration of trial 3.1 yrs 3.6 yrs 3.8 yrs 2.05 yrs

Baseline HbA1c 8.1% 8.2% 8.7% 8.7%

Primary endpoint1 ↓14% (1% to 26%) ↓14% (3% to 25%) ↓13% (2% to 22%) ↓26% (5% to 42%)

CV death ↓38% (23% to 51%) ↓13% (-6% to 28%) ↓22% (7% to 34%) ↓2% (-48% to 35%)

MI ↓13% (-9% to 30%) ↓15% (-5% to 31%) ↓12% (-3% to 25%) ↓26% (-8% to 49%)

Stroke ↑24% (-8% to 67%) ↓10% (-15% to 29%) ↓11% (-11% to 28%) ↓39% (1% to 72%)

HF hospitalization ↓35% (15% to 50%) ↓33% (13% to 48%) ↓13% (-5% to 27%) ↑11% (-23% to 61%)

Noteworthy adverse effects Genitourinary infections, no

excess DKA

Genitourinary infections,

Increased amputations

More gallstones, GI side

effects

Higher retinopathy rates

Likely broad mechanisms of

benefit

Rapid effects suggest a

hemodynamic or metabolic benefit, although a vascular

benefit may also occur

Lower overall event rates may

have attenuated outcomes benefits compared with

EMPA-REG

Slower effects suggest

benefits via less atherothrombosis and/or

avoidance of hypoglycemia

Slower effects suggest

benefits via less atherothrombosis

1Primary endpoint = 3-point MACE (death from CV causes, nonfatal MI, nonfatal stroke)

Sattar, et al. JACC vol. 69. No. 21, 2017

CV Disease Prevention in Diabetics

Opportunity Knocks

• 50-60% of ALL diabetics will die a cardiovascular death

• Diabetics with cardiovascular disease

– Very high risk of death, heart failure, MI, stroke

– Risk exists even with excellent care of blood pressure and lipids

– The risk is imminent

– Risk of heart failure and CV death is especially pressing

• New CV outcomes trials

– Powerful new information about tools to prevent CV events

– Work quickly….not decades but months to see benefits

– SGLT2 inhibitors effects on HF and CV death very rapid

– GLP-1 agonists a little slower

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CV Disease Prevention in Diabetics

Opportunity Knocks

• Role of cardiolovascular specialists

– Pay attention to diabetes and learn the drugs

– Don’t be afraid to order HbA1c’s

– Suggest initiating SGLT2 inhibitor or GLP-1 agonist when benefit perceived

– Dabble in prescribing

– Collaborate and communicate with primary care and endocrinology