Presenter Disclosure Information · Results into Practice Carol Hatch Wysham, MD Clinical Professor...
Transcript of Presenter Disclosure Information · Results into Practice Carol Hatch Wysham, MD Clinical Professor...
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