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Bryan Cardiology ConferenceDM2 & Cardiovascular

Outcome TrialsShannon Wakeley MD

Complete Endocrinology9/2/2017

Disclosures

• Speakers Bureau: Astra Zeneca, Sanofi, Abbvie, Boehringer-Ingelheim, Medtronic, Valeritas, Novo Nordisk

• Research: Medtronic

Objectives

• Review current DM2 guidelines (ADA vs AACE)

• Review available classes of DM2 meds -highlight most recently approved FDA medications

• Discuss cardiovascular outcome studies

• Discuss customization of medication regimen to individual patients.

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ADA GUIDELINES

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AACE GUIDELINES

New DM2 Medications

• 12 classes of DM2 meds

• Since 2010: 18 new FDA approved drugs to treat DM2

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Victoza (liraglutide);, Approved January 2010

Tradjenta (linagliptin); Approved May 2011

Bydureon (exenatide extended-release for injectable suspension); Approved January 2012

Jentadueto (linagliptin plus metformin hydrochloride); Approved February 2012

Invokana (canagliflozin); Approved April 2013

Nesina (alogliptin); ]Approved January 2013

Afrezza (insulin human) Inhalation Powder; Approved June 2014

Farxiga (dapagliflozin); January of 2014

Jardiance (empagliflozin) ; Approved August 2014

Tanzeum (albiglutide); Approved April 2014

Trulicity (dulaglutide); Approved September 2014

Xigduo XR (dapagliflozin + metformin hydrochloride); Approved October 2014

Synjardy (empagliflozin and metformin hydrochloride) Approved August 2015

Tresiba (insulin degludec injection); Approved September 2015

Adlyxin (lixisenatide);Approved July 2016

Soliqua 100/33 (insulin glargine and lixisenatide injection); Approved November 2016

Xultophy 100/3.6 (insulin degludec and liraglutide injection); Approved November 2016

Qtern (dapagliflozin and saxagliptin); Approved February 2017

“New Era” DM treatment

• Half of patients are not at goal (A1C <7%)

• Is step wise approach a “treat to fail” model?

• Combine meds to address the physiologic defects present in DM2

• Tailor treatment regimen to the patient.

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Metformin

-Has been used successfully since the 1950s as 1st line therapy for DM2-Biguanide - decreases blood glucose concentration by enhancing insulin sensitivity, inducing greater peripheral uptake of glucose and decreasing hepatic glucose output. -Lowers A1C by 1.5%-Generally well tolerated with weight gain, most common side effect GI issues-UKPDS demonstrated 36% relative risk reduction in all cause mortality and 39% relative risk reduction in MI

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SGLT2 inhibitors(sodium/glucose cotransporter 2)

BRAND NAME ACTIVE INGREDIENTS

Invokana canagliflozin

Invokamet (Invokamet XR) canaglifozin + metformin

Farxiga dapagliflozin

Xigduo XR dapagliflozin + metformin XR

Jardiance empagliflozin

Glyxambi empagliflozin + linagliptin

Synjardy empagliflozin + metformin

DPP4 inhibitors (dipeptidyl peptidase inhibitor)

BRAND NAME ACTIVE INGREDIENT

Januvia Sitagliptin

Janumet Sitagliptin + Metformin

Onglyza Saxagliptin

Kombiglyze XR Onglyxa + Metformin XR

Tradjenta Linagliptin

Jentadueto Linagliptin + Metformin

Glyxambi Linagliptin + Empagliflozin

Nesina Alogliptin

Oseni Alogliptin + Pioglitazone

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GLP1-Receptor Agonists

DRUG

Generic Dosing

ScheduleMixing

Required

Pre-

injection

Wait Time

Dosing Smallest

Needle

Guage

Needles

Included

Approved

with

Basal

Insulin

Auto

Injection

Byetta

Exenetide BID NO NO 5mcg,

10mcg

32g

4mm

NO YES NO

Adlyxin

Lixisenetide QD No No 10mcg,

20mcg

32g

4mm

NO YES NO

Bydureon

Pen

Exenetide

ER

Q WEEK YES NO 2mg 23g

7mm

YES NO NO

Tanzeum

Albiglutide Q WEEK YES YES

15-30 MIN

30mg,

50mg

29g

5mm

YES YES NO

Trulicity

Dulaglutide Q WEEK NO NO 0.75mg

1.5mg

29g

5mm,

built in

needle

YES, part

of the

device

YES YES

Victoza

Liraglutide Q DAY NO NO 0.6mg,

1.2mg,

1.8mg

32g

4mm

NO YES NO

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Combination basal insulin +GLP1 RA

• Soliqua 100/33 - 100 units glargine u100 (lantus) + 33mcg lixisenatide

• Xultophy 100/3.6 -100 units dulaglutide (tresiba) + 3.6mcg liraglutide (victoza) in each mL

• - 2 meds in one pen, addressing fasting and postprandial glucose levels.

Cardiovascular Disease

• CVD is the leading cause of morbidity & mortality for those with diabetes.

• Largest contributor to direct/indirect costs

• Common conditions coexisting with type 2 diabetes (e.g., hypertension, dyslipidemia) are clear risk factors for ASCVD.

• Diabetes itself confers independent risk

• Control individual cardiovascular risk factors to prevent/slow CVD in people with diabetes.

• Systematically assess all patients with diabetes for cardiovascular risk factors.

American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-S87

Cardiovascular Outcome Trials (CVOT)

• FDA mandates all DM meds be tested for adverse CV effects (rosiglitazone)

• During the quest to ensure no adverse CV outcomes we’ve found benefit!

• EMPA-REG

• CANVAS

• LEADER

• SUSTAIN-6

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EMPA-REG• Multicenter, randomized, double-blind, placebo-

controlled trial of >7000 patients from 42 countries with DM2 at high risk for CV events (*established CV disease).

• Empagliflozin 10mg or 25mg added to standard of care compared with placebo added to standard of care (glucose-lowering agents and CV drugs).

• Mean age 63 yrs, 57% had DM2 >10 yrs duration, 99% had established CV disease

• Primary endpoint: time to first occurrence of CV death, non-fatal heart attack or nonfatal stroke

EMPA-REG• Over 3.1 years, empagliflozin significantly reduced the composite

outcome of CV death, MI or stroke by 14%—->10.5% vs. 12.1% (HR 0.86; 95% CI 0.74-0.99; superiority P=0.04, noninferiority P<0.001; NNT 62)

• Risk of CV death reduced by 38%—>3.7% vs. 5.9% (HR 0.62; 95% CI 0.49-0.77; P<0.001; NNT 45)

• **FDA added new indiction for empagliflozin to reduce the risk of CV death in adults with DM2 and CV disease.

• 32% reduction in all-cause mortality and 35% reduction in hospitalization for heart failure.—->5.7% vs. 8.3% (HR 0.68; 95% CI 0.57-0.82; P<0.001; NNT 38)

• HF hospitalization or CV mortality excluding fatal stroke—->5.7% vs. 8.5% (HR 0.66; 95% CI 0.55-0.79; P<0.001; NNT 36)

• No difference between 10mg and 25mg dose

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June 12, 2017

CANVAS• Mean age 63 y/o, DM2 duration 13.5 yrs, 65% with CV disease.

• primary outcome: composite of death from CV disease, MI or stroke

• Primary outcome was 14% lower with canagliflozin (26.9 vs 31.5 pts/1000 pt years, HR 0.86, CI 0.75-0.97, P<0.02

• Although not statistically significant , realists showed a possible benefit with respect to progression of albuminuria and composite outcome of a sustained 40% reduction in eGFR, the need for renal-replacement therapy or death from renal causes.

• canagliflozin showed increased risk of amputation, primarily at level of the toe or metatarsal (6.3 vs 3.4 participants/1000 pt years, HR 1.987, CI 1.41-2.75)

*Amputation 6.3 (canagliflozin) vs 3.4 (placebo) /1000 pt yrs

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What’s driving the CV benefits?

Unclear, there are several theories (and studies underway to better define the physiology)

Theories - pleiotropic effects have been inferredV..

improved glucose control, lowering of BP, decrease in intraglomerular

pressure, reunion in albuminuria and amelioration of volume overload are all

plausible protective mechanisms.

SGLT2i: glucosuria & natriuresis - cause weight loss, amelioration of volume overload shift

from glucose to lipid metabolism - increase FFA, taken up by liver, more metabolism of FFA

to B-OHB ketone bodies

In the fasted state the human heart utilizes B-OHB.

B-OHB is an efficient fuel source - cardiomyocytes metabolize ketones more

easily thereby reducing oxygen demand.

In setting of stress and hypoxia the relative volume depletion results in elevated Hct -

thereby allowing more oxygen to be transported to cells

LEADER

Multicenter, double-blind, placebo-controlled trial at 410 sites in

32 countries. 9340 high-risk adults with DM2 followed for 3.5-5

years, randomly assigned to receive 1.8mg liraglutide daily vs

placebo

Mean age 64 years, DM2 duration ~13 yrs, >80% had established

CV disease

Primary endo point was time to first occurrence of the 3-point

major adverse cardiac event (MACE) components: CV death,

nonfatal MI, or nonfatal stroke

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LEADER13% risk reduction for MACE in liraglutide group(608 of 4668

patients taken liraglutide) vs 14.9% in placebo (694 of 4672 taking

placebo), including a 22% lower rate of CV death (4.7 vs 6.0%,

p=.007)

Time-to-event analysis of death from cardiovascular from causes,

nonfatal (including silent) myocardial infarction, or nonfatal

stroke.Hazard ratio 0.87; 95% CI, 0.78-0.97; P<0.001, NNT=53

Death from any cause: Hazard ratio 0.85; 95% CI, 0.74-0.97;

P=0.02, NNT=71

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SUSTAIN-6SUSTAIN-6: The culmination of a global phase 3 clinical development program for semaglutide injection (once weekly GLP1), comprising six trials and encompassing more than 7000 people with type 2 diabetes.

In the trial, approximately 3,300 people with type 2 diabetes were treated for 104 weeks.

The primary endpoint of the study was defined as the composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

The trial achieved its primary endpoint of showing non-inferiority of major cardiovascular events (MACE) with semaglutide compared with placebo, as well as a statistically significant reduction in stroke.

Mean age 63, DM2 x 13.9 yrs, mean A1C 8.7%

*Currently not approved anywhereV.working on oral version.

GLP1RA

studiesLEADER

(Victoza)

SUSTAIN-6(Semaglutide)

Patients (N) 9341 3297

Study Design:Primary

PreventionNo(19%) N (17%)

SecondaryPrevention

Yes (81%) Yes (83%)

Available Data June 2016 Sept 2016

Inclusion in LabelExpected 2H2017

Expected 2H2017

Outcome3-pointMACE

HR, 0.87p=0.01 (for superiority)

HR, 0.74p=0.02 (for superiority)

Driving FActor

Reduction in CV Death by 22%

Reduction in nonfatal stroke by 39%

SGLT2i

studiesCANVAS/CANVAS-R

(Invokana)

EMPA-REG

(Jardiance)DECLARE

(Farxiga)

Patients (N) 10,039 7034 17,150

Study Design:

PrimaryPrevention

Yes No Yes

SecondaryPrevention

Yes Yes (99%) Yes

Available Data 2017 Sept 2015Interim analysis

1Q20-17

Full Readout: 2019

Inclusion in Label

Pending 2018Expected 4Q2016

Pending 2020

Outcome3-pointMACE

HR 0.86p=0.02 (for superiority)

HR, 0.86p=0.04 (for superiority)

Pending

Driving FActor

Composite CV death, MI, stroke

Reduction in CV Death by 38%

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New Recommendation: Pharmacologic Therapy For T2DM

• In patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic cardiovascular disease, empagliflozinor liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care. Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes. B

American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

What about my patients?

• Tailor to their needs, their comorbidities, GFR, tolerability, lifestyle

• Avoid meds contraindicated in certain clinical scenarios (recurrent UTI’s, GMI, gastroparesis, renal impairment, hx pancreatitis, MTC/MEN2)

• Multiple options - use to patient’s advantage

• Your own comfort level

• $$

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Summary

• CV safety studies showing positive outcomes -shaping current guidelines

• Refer to AACE & ADA guidelines; Central to both -individualization of therapy (goal A1C, efficacy, side effects ~positive & negative, renal function, comorbid conditions, cost, coverage,

• Future treatmentsV oral GLP1RA, the race to the artificial pancreas, CGM coverage.

ReferencesGarber et al. Consensus Statement by the American Association of Clinical Endocrinologists and American

College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2017 Executive

summary. Endocrine Practice Vol 23 No. 2 February 2017

Holman R “Metformin as first choice in oral diabetes treatment: the UKPDS experience” Journ Annu Diabetol Hotel Dieu 2007:13-20,

Marso SP, Daniels GH, Buse JB, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J

Med 2016;375:312-322

Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patiets with type 2 diabetes and acute coronary

syndrome. N Engl J Med 2015;373:2247-57.

Zinman B, Wanner C Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2

diabetes. N Engl J Med 2015;373:2117-28.

Standards of Medical Care in Diabetes - 2017. Diabetes Care 2017;40(Suppl. 1):S1–S2

Neal et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes, N Engl J Med 2017;376:1-

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