Cardiovascular Disease and An1-‐hyperglycemic Agents
Lenley Adams, MD FRCPC FACP
Diabetes Ma@ers May 12, 2017
Presenter Disclosure
• Presenter: Lenley Adams, MD FRCPC FACP
• Rela,onships with commercial interests: – Advisory Board: NovoNordisk, Sanofi, Medtronic, Merck – Speakers Honoraria: AstraZeneca, NovoNordisk, Sanofi, Medtronic,
Merck, Boehringer Ingelheim/Lilly, Janssen, Valeant
Objec1ves
• Understand the rela1onship between CVD and diabetes
• Review the evidence for CV safety for newer an1-‐hyperglycemic agents
• Iden1fy individuals who might benefit from these agents
Diabe1c Complica1ons Stroke 2-‐ to 4-‐fold increase in cardiovascular mortality and stroke3
Cardiovascular Disease 8/10 diabe1c pa1ents die from CV events4
Diabe,c Neuropathy Leading cause of non-‐trauma1c lower extremity amputa1ons5
Diabe,c Re,nopathy Leading cause of
blindness in working-‐age adults1
Diabe,c Nephropathy
Leading cause of end-‐stage renal
disease2
1. Fong DS et al. Diabetes Care 2003;26(Suppl 1):S99-‐S102. 2. Molitch ME et al. Diabetes Care 2003;26 (Suppl 1):S94-‐S98. 3. Kannel WB et al. Am J Heart 1990;120:672-‐6. 4. Gray RP and Yudkin JS. In: Textbook of Diabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003;26(Suppl 1):S78-‐S79.
MI at a younger age among those with diabetes
20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85
MI, myocardial infarc1on Booth GL et al. Lancet. 2006;368:29–36.
Age group
0.5
1.0
1.5
2.0
2.5
3.0
0
No. events p
er 100 person-‐years
All lines fi@ed according to a polynomial equa1on; R2= 0.99–1.00 for each.
Diabetes n = 379,003 No diabetes n = 9,018,082 Database 1994-‐2000
No diabetes Men Women
Diabetes Men
Women
No diabetes Diabetes Men Women
UKPDS: Lowering A1C Reduces Risk Of Complica1ons IN T2DM
Adapted from Stra@on IM, et al. BMJ. 2000;321:405–412.
1% decrease of A1C correlates with the following risk reduc,on:
Prospec1ve observa1onal analysis of UKPDS35 pa1ents (n = 4585, incidence analysis; n = 3642, rela1ve risk analysis).; Median 10.0 years of follow up.*P<0.0001
Lower-‐extremity amputa1on or fatal peripheral vascular
disease*
Microvascular disease*
Cataract extrac1on*
Heart failure*
Myocardial infarc1on*
Stroke*
Cardiovascular complica1ons
43% 37% 19% 16% 14% 12%
The incidence of clinical complica/ons was significantly associated with glycemia
UKPDS: CONTINUED LONG-‐TERM BENEFITS–10 YEARS
POST-‐TRIAL
Holman et al. NEJM 2008;359:1577-‐89.
The positive legacy effect of early and intensive glucose control
Any diabetes- related endpoint
Microvascular disease
Myocardial infarction
All-cause mortality
At the end of post-trial follow-up (median 8.5 years). †Significant reduction on intensive therapy vs. conventional therapy.
-9%†
-24%†
-15%†
-13%†
reduced relative risk reduced relative risk reduced relative risk reduced relative risk
10 year post-trial follow-up of UKPDS demonstrated continued significant relative risk reduction of developing complications in patients
receivingintensive vs. conventional therapy
Conven,onal arm Intensive arm
MD follows clinical prac1ce guidelines
Therapies to achieve targets in glycemia, lipids, BP and microalbuminuria Mul1disciplinary care q3mo ASA and ACE inhibitors (independent of BP)
BP, blood pressure; CABG, coronary artery bypass graking; CV, cardiovascular; MI, myocardial infarc1on; PCI, percutaneous coronary interven1on; PVD, peripheral vascular disease. Gaede P et al. N Engl J Med. 2003;348:383–393.
What are the benefits of multifactorial interventions to achieve targets with respect to CV protection?
Type 2 diabetes + Microalbuminuria
n = 160
8-year follow-up composite outcome: CV death, MI, CABG, PCI, stroke,
amputation, or PVD surgery
Intensive group achieved targets
STENO 2
<4.5 mmol/L <1.7 mmol/L
• Aker 7.8 years, intensive therapy reduced: – CVD by 53% – Nephropathy by 61% – Re1nopathy by 48% – Autonomic neuropathy by 63%
Legacy effect observed: • 21.2 years aker interven1on start,
intensive therapy had reduced: – CVD by 51% – Mortality by 45% – Re1nopathy by 33% – Nephropathy by 48%
• Median 1me before first CV event was 8.1 years longer in the intensive group
Gaede P et al. N Engl J Med. 2003;348:383–393; Gaede P et al. Diabetologia. 2016;59:2298–2307.
What are the benefits of multifactorial interventions to achieve targets with respect to CV protection?
STENO 2 after 7.8 years
Diabetes Mellitus status in Canada Survey (DM-‐SCAN) 2013 Results: Guideline Targets Achieved
12
% of p
a1en
ts
50% 57%
36%
13%
0%
20%
40%
60%
A1C (≤7%) (n=5103)
LDL (≤2.0 mmol/L) (n=5069)
SBP/DBP (<130/80 mm HG) (n=5099)
All 3 Endpoints
(A1C, LDL, BP) (n=5104)
Adapted from Leiter LA et al. Can J Diabetes 2013;37:82-‐89.
Data regarding current management of T2DM was collected from 479 primary care physicians across Canada
Vascular Protection Checklist ü A • A1C – optimal glycemic control (usually ≤7%) ü B • BP – optimal blood pressure control (<130/80) ü C • Cholesterol – LDL ≤2.0 mmol/L if decided to
treat ü D • Drugs to protect the heart (regardless of baseline BP or LDL)
A – ACEi or ARB │ S – Statin │ A – ASA if indicated
ü E • Exercise / Eating healthy – regular physical activity, achieve and maintain healthy body weight
ü S • Smoking cessation
2013
Insulin Secretagogues
Thiazolidinediones DPP-‐4 Inhibitors and GLP-‐1 Agonists
Liver Adipose Tissues Muscles PancreasIntestine
Alpha-‐glucosidase Inhibitors
Delay the absorp,on of glucose from starch and sucrose
Biguanides Reduce hepa,c
gluconeogenesis Sulfonylureas and
megli,nides s,mulate insulin secre,on
Improve insulin resistance
Increase insulin secre,on, inhibit glucagon secre,on
An1hyperglycemic Medica1ons: MECHANISM OF ACTION
16 Adapted from Krentz AJ, Bailey CJ. Drugs 2005;65:385-‐411.
SGLT2 Inhibitors
Kidneys
Reduce the reabsorp,on of glucose by the kidneys: glucosuria
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association
CHOICE OF AGENT AFTER INITIAL METFORMIN
NEEDS TO BE
INDIVIDUALIZED Weight A1C
Hypoglycemia Comorbidi,es Coverage
(CV benefit)
Insulin
ORIGIN Trial: No Impact on Myocardial infarc1on, stroke or death
from CV Causes
Adapted from Origin Trial Inves1gators. NEJM 2012;367(4):
Similar results were found for other endpoints of revasculariza1on, conges1ve heart failure, death from any cause and cancers
0 1 2 3 4 5 6 7 0.0
0.1
0.2
0.3
0.4
Years of follow-‐up
Standard care
Insulin glargine
Adjusted hazard ra1o, 1.02 (0.94-‐1.11) P=0.63 by log-‐rank test
Prop
or1o
n with
events
21 h@p://journals.plos.org/plosone/ar1cle?id=10.1371%2Fjournal.pone.0153594
Sulphonylurea
SU
• CONCLUSIONS: The present meta-‐analysis showed an associa1on between SU therapy and a higher risk of major cardiovascular disease-‐related events compared with other glucose lowering drugs. Results of ongoing RCTs should be available in 2018
Bain S, Druyts E, Balijepalli C, et al. Cardiovascular events and all-‐cause mortality associated with sulphonylureas compared with other an,hyperglycaemic drugs: A Bayesian meta-‐analysis of survival data. Diabetes Obes Metab. 2016 Nov 14
Bain S, Druyts E, Balijepalli C, et al. Cardiovascular events and all-‐cause mortality associated with sulphonylureas compared with other an,hyperglycaemic drugs: A Bayesian meta-‐analysis of survival data. Diabetes Obes Metab. 2016 Nov 14
Newer agents
Tomlinson et al. EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2016 VOL. 12, NO. 11, 1267–1271
DPP4 Inhibitors
CV Outcome Trials: DPP-‐4 Inhibitors
30 Golden SH. Am J Cardiol 2011; 108(Suppl):59B-‐67B; Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B; www.clinicaltrials.gov
Trial Therapies # Population Primary endpoint End Date
EXAMINE Aloglip1n/Placebo 5400 ACS 15-‐90 days
before Non-‐inferiority: 1me to occurrence of MACE PUBLISHED
SAVOR Saxaglip1n/Placebo 16,500 CVD or ≥ 2 RF
Superiority efficacy, non-‐inferiority safety: composite CV death, NF MI, NF stroke
PUBLISHED
CARMELINA Linagliptin/Placebo 8,300 High risk of CV
events Time to first occurrence of composite CV outcome Jan 2018
CAROLINA Linagliptin/ Glimepiride 6000 CVD or ≥ 2 RF
Non-inferiority: time to first occurrence of any component of MACE composite outcome
Sept 2018
TECOS Sitagliptin/ Placebo 14,000 Established CVD
Non-inferiority: time to first occurrence of composite CV outcome
PUBLISHED
ACS: Acute coronary syndrome; CVD: Cardiovascular disease; RF: Risk factor
Study Drug n/N (%)
Placebo n/N (%)
Hazard Ra,o
95% CI
P Value
SAVOR-‐TIMI 53 (saxaglip1n vs. placebo)
613/8280 (7.4%)
609/8212 (7.4%) 1.00 0.89, 1.12 0.99
EXAMINE (aloglip1n vs. placebo)
305/2701 (11.3%)
316/2679 (11.8%) 0.96 NA, 1.16 0.315
TECOS (sitaglip1n vs. placebo)
745/7332 (10.2%)
746/7339 (10.2%) 0.99 0.89, 1.10 0.844
SAVOR + EXAMINE + TECOS
1663/18313 (9.1%)
1671/18230 (9.2%) 0.99 0.92, 1.06
Primary End Points of DPP-‐4 Inhibitor CVOT
31 White WB et al. N Engl J Med. 2013;369:1327-‐35; Scirica BM et al. N Engl J Med. 2013;369:1317-‐26; Green JB et al. N Engl J Med. 2015 doi: 10.1056/NEJMoa1501352
CVOT: Cardiovascular outcomes trial; NA: Not available
Favours Treatment
Favours placebo
0 1 2
Study Drug
n/N (%)
Placebo n/N (%)
Hazard
Ra,o
95% CI
P Value
SAVOR-‐TIMI 53 (saxaglip1n vs. placebo)
289/8280 (3.5%)
228/8212 (2.8%) 1.27 1.07, 1.51 0.009
EXAMINE (aloglip1n vs. placebo)
106/2701 (3.9%)
89/2679 (3.3%) 1.19 0.89, 1.58 0.238
TECOS (sitaglip1n vs. placebo)
228/7332 (3.1%)
229/7339 (3.1%) 1.00 0.83, 1.20 0.983
SAVOR + EXAMINE + TECOS
623/18313
(3.4%)
546/18230
(3.0%) 1.14 0.97, 1.34
Hospitaliza1on for Heart Failure: EXAMINE, SAVOR-‐TIMI 53, and TECOS
32 White WB et al. N Engl J Med. 2013;369:1327-‐35; Scirica BM et al. N Engl J Med. 2013;369:1317-‐26; Green JB et al. N Engl J Med. 2015 doi: 10.1056/NEJMoa1501352
Favours Treatment
Favours placebo
0 1 2
SGLT2 Inhibitors
SGLT2 Inhibitors: Trials with Primary Cardiovascular Outcomes
34 h@p://clinicaltrials.gov; Zinman B, et al. NEJM 2015; 373(22): 2117-‐28
Treatment N Popula,on Endpoints End Date
CANVAS Canagliflozin
vs. Placebo
4,407 CVD or high risk for CVD
CV death, non-‐fatal MI or
non-‐fatal CVA
June 2017
DECLARE Dapagliflozin
vs. Placebo
17,150 CVD or high risk for CVD
CV death, non-‐fatal MI or
non-‐fatal CVA
April 2019
EMPA-‐REG Outcome
Empagliflozin vs.
Placebo 7,020 CVD
CV death, non-‐fatal MI or
non-‐fatal CVA PUBLISHED
CANVAS: Canagliflozin Cardiovascular Assessment Study; DECLARE: Dapagliflozin Effect on Cardiovascular Events; CVD: cardiovascular disease; MI: myocardial infarc1on; CVA: cerebrovascular accident; CV: Cardiovascular; MI: Myocardial infarc1on; RF: Risk factor
Zinman B, et al. NEJM 2015; 373(22): 2117-‐28 35
CVD, defined by > =1 of the following: MI >2 months prior, Mul1vessel CAD, Single vessel CAD with posi1ve stress test or UA hospitaliza1on in prior year, UA >2 months prior and evidence of CAD, Stroke >2 months prior , Occlusive PAD
Baseline characteris1cs: CV complica1ons
37 Zinman B, et al. NEJM 2015; 373(22): 2117-‐28.
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342) Any CV risk factor 2307 (98.9%) 2333 (99.5%) 2324 (99.2%) Coronary artery disease 1763 (75.6%) 1782 (76.0%) 1763 (75.3%) Mul1-‐vessel coronary artery disease 1100 (47.1%) 1078 (46.0%) 1101 (47.0%)
History of MI 1083 (46.4%) 1107 (47.2%) 1083 (46.2%) Coronary artery bypass grak 563 (24.1%) 594 (25.3%) 581 (24.8%)
History of stroke 553 (23.7%) 535 (22.8%) 549 (23.4%) Peripheral artery disease 479 (20.5%) 465 (19.8%) 517 (22.1%) Single vessel coronary artery disease 238 (10.2%) 258 (11.0%) 240 (10.2%)
Cardiac failure* 244 (10.5%) 240 (10.2%) 222 (9.5%) Data are n (%) in pa1ents treated with ≥1 dose of study drug
CV: Cardiovascular;MI: Myocardial infarc1on
LDL cholesterol, mmol/L 4.7 (2.0) 4.8 (2.0) 4.8 (2.0) HDL cholesterol, mmol/L 2.4 (0.6) 2.5 (0.7) 2.5 (0.7) eGFR, mL/min/1.73m2 (MDRD) 73.8 (21.1) 74.3 (21.8) 74.0 (21.4) ≥90 mL/min/1.73m2 488 (20.9%) 519 (22.1%) 531 (22.7%) 60 to <90 mL/min/1.73m2 1238 (53.1%) 1221 (52.1%) 1204 (51.4%) <60 mL/min/1.73m2 607 (26.0%) 605 (25.8%) 607 (25.9%)
Systolic blood pressure, mmHg 135.8 (17.2) 134.9 (16.8) 135.6 (17.0) Diastolic blood pressure, mmHg 76.8 (10.1) 76.6 (9.8) 76.6 (9.7) Heart rate, bpm* 70.7 (0.2) 71.0 (0.2) 70.5 (0.2)
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342) Body mass index, kg/m2 30.7 (5.2) 30.6 (5.2) 30.6 (5.3) Weight, kg 86.6 (19.1) 85.9 (18.8) 86.5 (19.0) Waist circumference, cm 105.0 (14.0) 104.7 (13.7) 104.8 (13.7)
Baseline characteris1cs: CV risk factors
38 Zinman B, et al. NEJM 2015; 373(22): 2117-‐28.
Data are n (%) or mean (SD) in pa1ents treated with ≥1 dose of study drug *Mean (SE). LDL: Low density lipoprotein; HDL: High density lipoprotein; eGFR: Es1mated glomerular filtra1on rate; MDRD: Modifica1on of Diet in Renal Disease equa1on
Empagliflozin Placebo HR (95% CI) p-‐value
3-‐point MACE 490/4687 282/2333 0.86 (0.74,
0.99)* 0.0382
CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001
Non-‐fatal MI 213/4687 121/2333 0.87 (0.70,
1.09) 0.2189
Non-‐fatal stroke 150/4687 60/2333 1.24 (0.92,
1.67) 0.1638
0.25 0.50 1.00 2.00
CV death, MI and stroke
41 Zinman B, et al. NEJM 2015; 373(22): 2117-‐28.
Favours empagliflozin Favours placebo
*95.02% CI, Cox regression analysis. MACE: Major Adverse Cardiovascular Event; HR: Hazard ra1o; CV: Cardiovascular; MI: Myocardial infarc1on;
CV Death
42 Zinman B, et al. NEJM 2015; 373(22): 2117-‐28.
HR 0.62 (95% CI: 0.49-‐0.77)
p<0.0001
Empagliflozin 10 mg HR 0.65 (95% CI: 0.50-‐0.85), p=0.0016
Empagliflozin 25 mg
HR 0.59 (95% CI: 0.45-‐0.77), p=0.0001
Cumula1ve incidence func1on. HR: Hazard ra1o
38%
Empagliflozin (pooled) Placebo
Empagliflozin
Hospitaliza1on for Heart Failure
43 Zinman B, et al. NEJM 2015; 373(22): 2117-‐28.
HR 0.65 (95% CI: 0.50-‐0.85)
p=0.0017
Empagliflozin 10 mg HR 0.62 (95% CI: 0.45-‐0.86), p=0.0044
Empagliflozin 25 mg
HR 0.68 (95% CI: 0.50-‐0.93), p=0.0166
Cumula1ve incidence func1on. HR: Hazard ra1o
35%
Empagliflozin (pooled) Placebo
Empagliflozin
EMPA-‐REG Outcome: Therapeu1c Considera1ons
• Empagliflozin, as used in this trial, for 3 years in 1,000 pa1ents with type 2 diabetes at high CV risk:
– 25 lives saved (82 vs. 57 deaths)
• 22 fewer CV deaths (59 vs. 37)
– 14 fewer hospitaliza1ons for heart failure (42 vs. 28)
– 53 addi1onal genital infec1ons (22 vs. 75)
Zinman B, et al. EASD 2015 Annual MeeEng. Available at: h@p://www.easdvirtualmee1ng.org/contentsessions/2030 Accessed October 2, 2015
Number needed to treat (NNT) to prevent one death across landmark trials in pa1ents with high CV risk
48
1. 4S inves1gator. Lancet 1994; 344: 1383-‐89, h@p://www.trialresultscenter.org/study2590-‐4S.htm; 2. HOPE inves1gator N Engl J Med 2000;342:145-‐53, h@p://www.trialresultscenter.org/study2606-‐HOPE.htm
Simvasta1n1 for 5.4 years
High CV risk 5% diabetes, 26% hypertension
1994 2000 2015
Pre-‐sta,n era
High CV risk 38% diabetes, 46%
hypertension
Ramipril2 for 5 years
Pre-‐ACEi/ARB era
<29% sta,n
Empagliflozin for 3 years
T2DM with high CV risk 92% hypertension
>80% ACEi/ARB
>75% sta,n
Empagliflozin Placebo
no. with event
/analyzed (%)
rate/ 1000 pt-‐yr
no. with event/
analyzed (%)
rate/ 1000 pt-‐yr
Hazard Ra1o (95% CI)
p-‐value
Incident or worsening nephropathy or CV death
675/4170 (16.2)
60.7 497/2102 (23.6)
95.9 0.61 (0.55–0.69) <0.001
Incident or worsening nephropathy 525/4124 (12.7)
47.8 388/2061 (18.8)
76.0 0.61 (0.53–0.70) <0.001
Progression to macroalbuminuria 459/4091 (11.2)
41.8 330/2033 (16.2)
64.9 0.62 (0.54–0.72) <0.001
Doubling of serum crea1nine* 70/4645 (1.5)
5.5 60/2323 (2.6)
9.7 0.56 (0.39–0.79) <0.001
Ini1a1on of renal replacement therapy 13/4687 (0.3)
1.0 14/2333 (0.6)
2.1 0.45 (0.21–0.97)
0.04
Doubling of serum crea1nine*, ini1a1on of renal replacement therapy, or death due to renal disease
81/4645 (1.7)
6.3 71/2323 (3.1)
11.5 0.54 (0.40–0.75) <0.001
Incident albuminuria in pa1ents with normoalbuminuria at baseline
1430/2779 (51.5)
252.5 703/1374 (51.2)
266.0 0.95 (0.87–1.04)
0.25
0.125 0.25 0.5 1.0 2.0 4.0 Favors placebo Favors empagliflozin
EMPAGLIFLOZIN REDUCES RENAL OUTCOMES (EMPA-‐REG OUTCOME)
50
Incident or worsening nephropathy was defined as progression to macroalbuminuria, doubling of serum crea,nine level, ini,a,on of renal-‐replacement therapy, or death from renal disease. Cox regression analyses in pa1ents treated with ≥1 dose of study drug. Analyses were prespecified except for the composite of doubling of serum crea1nine, ini1a1on of renal replacement therapy, or death due to renal disease. *Accompanied by eGFR [MDRD] ≤45 ml/min/1.73m2. Wanner C et al. NEJM 2016;doi:10.1056/NEJMoa1515920.
Hazard ra1o (95% CI)
GLP1 Receptor Agonists
Lixisena1de
Neutral
53 Marso SP et al. NEJM 2016;DOII:10.1056/NEJMoa1603827.
LEADER: Study design
Marso SP et al. NEJM 2016;DOII:10.1056/NEJMoa1603827. Presented at the American Diabetes Associa1on 76th Scien1fic Sessions, Session 3-‐CT-‐SY24. June 13 2016, New Orleans, LA, USA.
CV: cardiovascular; DPP-‐4i, dipep1dyl pep1dase-‐4 inhibitor; GLP-‐1RA: glucagon-‐like pep1de-‐1 receptor agonist; HbA1c: glycated hemoglobin; MEN-‐2: mul1ple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral an1diabe1c drug; OD: once daily; T2DM: type 2 diabetes mellitus.
Liraglu,de 0.6-‐ 1.8 mg + standard of care
Placebo + standard care
Safety follow up
Safety follow up
Placebo run-‐in
2 weeks 30 days
Randomiza1on (1:1) Double-‐blind
Screening End of treatment
Minimum dura,on 3.5 years Maximum 5 years
Maximum 611 primary events
Key inclusion criteria § T2DM, HbA 1c ≥7.0% § An1diabe1c drug naïve; OADs and/or basal/premix insulin
§ Age ≥50 years and established CV disease or chronic renal failure or
§ Age ≥60 years and risk factors for CV disease
Key exclusion criteria § T1DM § Use of GLP-‐1RAs, DPP-‐4i, pramlin1de, or rapid-‐ac1ng insulin
§ Familial or personal history of MEN-‐2 or MTC
Baseline cardiovascular risk profile
Marso SP et al. NEJM 2016;DOII:10.1056/NEJMoa1603827. Presented at the American Diabetes Associa1on 76th Scien1fic Sessions, Session 3-‐CT-‐SY24. June 13 2016, New Orleans, LA, USA.
Data are number of pa1ents (%). CHD: coronary heart disease; CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR: es1mated glomerular filtra1on rate; NYHA: New York Heart Associa1on; TIA: transient ischemic a@ack.
Liraglu,de (N=4668)
Placebo (N=4672)
Established CVD/CKD (age ≥50 years) 3831 (82.1) 3767 (80.6)
Prior myocardial infarc1on 1464 (31.4) 1400 (30.0)
Prior stroke or prior TIA 730 (15.6) 777 (16.6)
Prior revasculariza1on 1835 (39.3) 1803 (38.6) >50% stenosis of coronary, caro1d, or lower extremity arteries 1188 (25.4) 1191 (25.5)
Documented symptoma1c CHD 412 (8.8) 406 (8.7) Documented asymptoma1c cardiac ischemia 1241 (26.6) 1231 (26.3)
Chronic heart failure NYHA II – III 653 (14.0) 652 (14.0)
Chronic kidney disease (eGFR <60 mL/min/1.73m²) 1185 (25.4) 1122 (24.0)
Pa,ents with event/analyzed
HR (95% CI) p-‐value Lira Pbo
3-‐point MACE 0.87 (0.78-‐0.97) 0.01 608/4668 694/4672
CV death 0.78 (0.66-‐0.93) 0.007 219/4668 278/4672
Non-‐fatal MI 0.88 (0.75-‐1.03) 0.11 281/4668 317/4672
Non-‐fatal stroke 0.89 (0.72-‐1.11) 0.30 159/4668 177/4672
0.50 1.00
CV DEATH, MI AND STROKE
58 Marso SP et al. NEJM 2016;DOII:10.1056/NEJMoa1603827. Presented at the American Diabetes Associa1on 76th Scien1fic Sessions, Session 3-‐CT-‐SY24. June 13 2016, New Orleans, LA, USA.
Favors Lira Favors Pbo
*95.02% CI. CV: cardiovascular; Lira: liraglu1de; MACE: major adverse cardiovascular event; MI: myocardial infarc1on; Pbo: placebo.
1.50
Hazard ra1o (95% CI)
CV death
59 Marso SP et al. NEJM 2016;DOII:10.1056/NEJMoa1603827. Presented at the American Diabetes Associa1on 76th Scien1fic Sessions, Session 3-‐CT-‐SY24. June 13 2016, New Orleans, LA, USA.
Pa1e
nt with
an even
t (%)
4668 4641 4599 4558 4505 4445 4382 4322 1723 484
4672 4648 4601 4546 4479 4407 4338 4267 1709 465
Liraglu1de
Placebo
Pa,ents at risk
0
2
4
6
8
0 6 12 18 24 30 36 42 48 54 Time from randomiza1on (months)
The cumula1ve incidences were es1mated with the use of the Kaplan–Meier method, and the hazard ra1os with the use of the Cox propor1onal-‐hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the pa1ents had an observa1on 1me beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ra1o.
HR: 0.78 95% CI (0.66 – 0.93)
p=0.007
Placebo
Liraglu1de
22%
SUSTAIN 6-‐ Semaglu1de
CVD-‐REAL
Lower Rates of Hospitaliza1on for Heart
Failure and All-‐Cause Death in New Users of SGLT2 Inhibitors:
The CVD-‐REAL Study
Data presented at the 66th Annual Scien1fic Session of the American College of Cardiology, Washington, DC,
March 17–19, 2017
Expiry March 2018
This slide presenta1on may include evolving scien1fic informa1on that has not been reviewed and approved by Health Canada. These slides are intended for educa1onal purposes only. AstraZeneca Canada Inc. does not recommend the use of FORXIGA® in any other indica1on than as described in the Canadian Product Monograph.
Primary
• Compare risk of HHF in pa1ents with T2DM newly ini1ated on SGLT2 inhibitors versus other glucose-‐lowering drugs
Secondary
• Compare risk of all-‐cause death between the two treatment groups
• Compare risk of HHF or all-‐cause death between the two treatment groups
Study objec1ves
Kosiborod et al. ACC 2017; Washington DC [Presentation 415-14]
Inclusion criteria
• New users receiving SGLT2 inhibitors or other glucose-‐lowering drugs
• Established T2DM on or prior to the index date • ≥18 years old • >1 year* historical data available prior to the index date
Exclusion criteria
• Pa1ents with type 1 diabetes • Pa1ents with gesta1onal diabetes
Inclusion/exclusion criteria
*In Germany, >6 months
Kosiborod et al. ACC 2017; Washington DC [Presentation 415-14]
Contribu1on of SGLT-‐2 inhibitor: Cohort 1 HHF
52.7%
75.9%
1.8%
41.8%
19.0%
91.9%
5.5% 5.1% 6.3%
0
10
20
30
40
50
60
70
80
90
100
All countries combined
US only European countries combined
Prop
ortio
n of
expo
sure
tim
e (%
)
Canagliflozin Dapagliflozin Empagliflozin
HHF (N=309,046)
Kosiborod et al. ACC 2017; Washington DC [Presentation 415-14]
Hospitaliza1on for heart failure primary analysis
P-value for SGLT2 inhibitor vs other glucose-lowering drug: <0.001
Data are on treatment, unadjusted.
Heterogeneity p-value: 0.17
Kosiborod et al. ACC 2017; Washington DC [Presentation 415-14]
All-‐cause death primary analysis
P-value for SGLT2i vs other glucose-lowering drug: <0.001
Data are on treatment, unadjusted.
Heterogeneity p-value: 0.09
Kosiborod et al. ACC 2017; Washington DC [Presentation 415-14]
Nystrom et al Diabetes Obes Metab. 2017;1–11.
• Novel oral GLD treatment was associated with lower risk of all-‐cause mortality, CVD and severe hypoglycemia compared with insulin treatment.
• Dapagliflozin was associated with a lower risk of both all-‐cause mortality and CVD, whereas DPP-‐4 inhibitor treatment was only associated with lower risk of all-‐cause mortality.
Nystrom et al Diabetes Obes Metab. 2017;1–11.
75
Add another class of agent best suited to the individual (agents listed in alphabe/cal order):
Class Rela,ve A1C Lowering
Hypo-‐ glycemia
Weight Effect in Cardiovascular Outcome Trial
Other therapeu,c considera,ons Cost
α-‐glucosidase inhibitor (acarbose)
ê Rare Neutral to ê
Improved postprandial control, GI side-‐effects
$$
DPP-‐4 Inhibitors êê Rare Neutral to ê
alo, saxa, sita: Neutral
Cau1on with saxaglip1n in heart failure $$$
GLP-‐1R agonists êê toêêê
Rare
êê
lira: Superiority in T2DM pa1ents with
clinical CVD lixi: Neutral
GI side-‐effects
$$$$
Insulin êêê Yes éé glar: Neutral No dose ceiling, flexible regimens $-‐$$$$
Insulin secretagogue: Megli,nide Sulfonylurea
êê êê
Yes Yes
é é
Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide
$$ $
SGLT2 inhibitors êê toêêê
Rare êê empa: Superiority in T2DM pa1ents with clinical CVD
Genital infec1ons, UTI, hypotension, dose-‐related changes in LDL-‐C, cau1on with renal dysfunc1on and loop diure1cs, dapagliflozin not to be used if bladder cancer, rare diabe1c ketoacidosis (may occur with no hyperglycemia)
$$$
Thiazolidinediones êê Rare éé Neutral CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-‐12 weeks required for maximal effect
$$
Weight loss agent (orlistat)
ê None ê GI side effects $$$
alo=aloglip1n; glar=glargine; saxa=saxaglip1n; sita=sitaglip1n; lira=liraglu1de; lixi=lixisena1de; empa=empagliflozin
11/2016
Gillian B et al. CDA Guidelines: November 2016 Interim Update. Can J Diabetes.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association
Start metformin immediately
Consider initial combination with another
antihyperglycemic agent
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin
A1C <8.5% Symptomatic hyperglycemia
with metabolic decompensation
A1C ≥8.5%
Initiate insulin +/- metformin
If not at glycemic target
(2-3 mos)
Start / Increase
metformin If not at glycemic
targets
L I F E S T Y L E
Add another agent best suited to the individual by prioritizing patient characteristics:
Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Cardiovascular disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment
AT DIAGNOSIS OF TYPE 2 DIABETES
Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations, consider eGFR See cost column; consider access
PATIENT CHARACTERISTIC CHOICE OF AGENT
PRIORITY: Clinical Cardiovascular Disease
2016
Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide)
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association
Recommendation 4
4. In people with clinical cardiovascular disease in whom glycemic targets are not met, an SGLT2 inhibitor with demonstrated cardiovascular outcome benefit should be added to antihyperglycemic therapy to reduce the risk of cardiovascular and all-cause mortality [Grade A, Level 1A for empagliflozin].
2016
Choices aker Me�ormin
Individualize
• Is there established CV disease? • Do they meet the study inclusion criteria?
– Primary vs secondary preven1on
• More data to come • Real world data encouraging
Trial Limita1ons
• Dura1on • Applicability to lower risk pa1ents-‐ early DM2 • Lack of data on SU (observa1onal, CAROLINA) • Noninferiority