#diabetesmatters - cardiovascular disease and an1-‐ hyperglycemic agents - adams

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


non-‐fatal CVA

April 2019

EMPA-‐REG Outcome

Empagliflozin vs.

Placebo 7,020 CVD


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


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


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


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


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


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)


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


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


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.


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)


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

#diabetesmatters - cardiovascular disease and an1-‐ hyperglycemic agents - adams

Healthcare