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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-
10.