108/05/10 心臟衰竭的治療方法

Diabetes Care in the Future: From Latest Evidence to Clinical Practice 李美月 內分泌新陳代謝內科 高醫附設醫院

Outline • Risk factors, mortality, and CV outcomes in patients with type 2 diabetes • CV outcome trials of diabetic medication • The latest clinical guidelines in 2018 • Conclusion

2

Outline • Risk factors, mortality, and CV outcomes in patients with type 2 diabetes • CV outcome trials of diabetic medication • The latest clinical guidelines in 2018 • Conclusion

3

• A national cohort study included 271,174 patients with T2DM • Median follow-up 5.7 years • Swedish National Diabetes Register 4

Rawshani A et al. N Engl J Med. 2018 Aug 16;379(7):633-644.

Acute MI

Stroke

Relative Importance of Risk Factors for Predicting Acute MI and Stroke among Patients with Type 2 Diabetes

5

Rawshani A et al. N Engl J Med. 2018 Aug 16;379(7):633-644.

Patients without diabetes

Patients with more risk factors within target ranges are associated with lower risk of mortality Five risk factors: 1. Elevated A1c (≥7.0%) 2. Elevated LDL (≥2.5 mmol; 97 mg/dl) 3. Elevated BP (≥140/80 mm Hg) 4. Albuminuria (presence of microalbuminuria or macroalbuminuria) 5. Smoking (current smoker)

6

Rawshani A et al. N Engl J Med. 2018 Aug 16;379(7):633-644.

7

Heart Failure is still increased in patients with 5 risk factors within target ranges Rawshani A et al. N Engl J Med. 2018 Aug 16;379(7):633-644.

Mortality in Diabetic patients with and without Heart Failure in LIFE and RENAAL trial

HR for mortality: 5.98 (95% CI 3.90â&#x20AC;&#x201C;9.17), p<0.0001

HR, hazard ratio Lancet Diabetes Endocrinol. 2014 Oct;2(10):843-51.

HR for mortality: 3.99 (95% CI 3.02â&#x20AC;&#x201C;5.25), p<0.0001

The presence of HF in patients with diabetes is associated with an increased risk of death

1.00

Diabetes, without heart failure (n=69,083)

0.75

Proportion surviving

HR: 10.6

0.50

P <0.001

Diabetes with incident heart failure

0.25

(n=46,720)

0

0

1

2

3

Years

HF, heart failure; DRG, diagnosis related group Bertoni AG, et al. Diabetes Care. 2004;27:699–703.

4

5

• 115,803 adults 65 years and older with diabetes in fee-for-service Medicare without a prior HF claim were followed for 5 years • Incident HF was determined using DRG codes • Incident heart failure among older adults with diabetes was associated with high mortality— 32.7 per 100 person-years compared with 3.7 per 100 person- years

HFrEF

Heart Failure

(Heart failure with reduced ejection fraction)

HFpEF (preserved)

LVEF<40%

LVEF ≥50%

Endothelial inflammation ↓ Cardiac dysfunction

Myocardial injury (ex. post-MI)

10

http://trends.medicalexpo.com/project-43696.html European Heart Journal (2016) 37, 2129–2200

(ex.Diabetes, hypertension, obesity, metabolic syndrome, smoking)

~50% of all patients with heart failure have a normal EF

Current HFrEF therapeutic classes

中華民國心臟學會-心衰竭委員會: 心臟衰竭自我照護手冊 2016

In contrast, current HF classes with proven outcomes in HFrEF fail to improve outcomes in patients with HFpEF Trial

Drug (Class)

PEP-CHF1

Perindopril (ACE-I)

CHARM-Preserved2

Candesartan (ARB)

I-PRESERVED3

Irbesartan (ARB)

TOPCAT4

Spironolactone (Aldosterone antagonist)

Primary Endpoint

Results

Composite of all-cause mortality or unplanned heart failure related hospitalization

HR 0.92; (p=0.545)

Composite of CV death or unplanned admission to HR 0.89 hospital for the management of worsening HF (p=0.12)

Composite outcome of death from any cause or hospitalization for a CV cause (HF, MI, unstable angina, arrhythmia, or stroke).

HR 0.95; (p=0.35)

Composite of death from CV causes, aborted cardiac arrest, or hospitalization for the management of heart failure.

HR 0.89 (p=0.14)

Composite of heart failure hospitalization or heart failure mortality

HR 0.82 (p=0.136)

CV, cardiovascular; ACE, angiotensin converting enzyme; ACE-I, ACE inhibitor; ARB angiotensin receptor blocker; HR Hazard ratio 1. Cleland JG, et al. European DIG-preserved5 Heart Journal (2006) 27, 2338â&#x20AC;&#x201C;2345; 2. Yusuf s et al. Lancet 2003; 362: 777â&#x20AC;&#x201C;81. 3. Massie BM et al. N Engl J Med 2008;359:2456-67.4. Pitt B, et al N Engl J Med 2014;370:1383-92.. 5. Ahmed A et al. Circulation. 2006 Aug 1;114(5):397-403.

Digoxin

HF remains under-diagnosed in patients with T2D, suggesting a high index of suspicion is warranted 27.7% of a T2D population had undiagnosed HF • 581 patients aged 60 years or over with T2DM without cardiologist-confirmed diagnosis of HF • An expert panel used the criteria of the ESC (European Society of Cardiology) to diagnose HF • 27.7% were found to have previously unknown HF • The majority of newly detected HF had HFpEF • The prevalence of undiagnosed HF was higher: − increasing age, hypertension, females, BMI ≥30 kg/m2, patients with dyspnea, patients complaining of fatigue • Screening of patients with T2D should be considered given the high prevalence of previously unknown HF

BMI, body mass index; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; T2D, type 2 diabetes.

Boonman-de Winter LJ, et al. Diabetologia. 2012;55:2154–2162.

Criteria to establish diastolic and systolic dysfunction and heart failure • The patients underwent a standardized diagnostic assessment, which was executed in the cardiology outpatient department of the Admiraal de Ruyter Hospital in Goes.

• A standard 12-lead ECG was recorded and classified according to the Minnesota coding criteria by a single experienced cardiologist, blinded to all other test results.

• Echocardiography was performed with a General Electric, Vivid 7 imaging system device by well-trained and experienced cardiac sonographers.

- An E/e' ≥ 15 was considered abnormal, and these patients were classified as having diastolic dysfunction.

- Patients with E/e' between 8 and 15 and a septal e' <8 cm/s, who had echocardiographic left ventricular hypertrophy or elevated indexed LA volume or S/D < 1 were also classified as having diastolic dysfunction.

- Systolic dysfunction was defined as an LVEF ≤ 45% by echocardiography, and diastolic dysfunction graded as I, II or III in combination with an LVEF > 45%.

• Blood was taken within 2 weeks of the diagnostic assessment, with measurement of serum B-type natriuretic peptide (NT-proBNP).

• To be classified as heart failure, systolic or diastolic dysfunction had to be present in combination with one or more suggestive symptoms (e.g. orthopnoea, paroxysmal nocturnal dyspnoea, fatigue, peripheral oedema, nocturia more than twice a night) and one or more signs indicative of heart failure (e.g. peripheral or pulmonary fluid retention or raised jugular venous pressure). In patients who used diuretics, signs of volume overload were not obligatory to classify the presence of heart failure.

• The panel was guided by the diagnostic principles of the most recent guidelines for heart failure of the European Society of Cardiology (ESC).

Boonman-de Winter LJ, et al. Diabetologia. 2012;55:2154–2162.

European Heart Journal (2016) 37, 2129â&#x20AC;&#x201C;2200

Outline • Risk factors, mortality, and CV outcomes in patients with type 2 diabetes • CV outcome trials of diabetic medication • The latest clinical guidelines in 2018 • Conclusion

16

Rosiglitazone Meta-analysis: Increased Rates of MI and CV Death from CV Causes Study

Rosiglitazone Group

Control Group

Odds Ratio

P Value

No. of events/total no. (%) Steven E. Nissen Cardiologist

MI

Small trials combined

44/10,285 (0.43)

22/6106 (0.36)

1.45 (0.88-2.39)

0.15

DREAM

15/2635 (0.57)

9/2634 (0.34)

1.65 (0.74-3.68)

0.22

ADOPT

27/1456 (1.85)

41/2895 (1.42)

1.33 (0.80-2.21)

0.27

1.43 (1.03-1.98)

0.03

Overall Death from CV causes

17

Small trials combined

25/6845 (0.36)

7/3980 (0.18)

2.40 (1.17-4.91)

0.02

DREAM

12/2635 (0.46)

10/2634 (0.38)

1.20 (0.52-2.78)

0.67

Nissen SE, et al. N Engl J Med. 2007;31.

Nissen SE et al. N Engl J Med. 2007 Jun 14;356(24):2457-71

FDA (2008) and EMA (2012) Now Requires CVOTs With New Submissions in New Antidiabetic Therapies •

Owing to the potential for CV risk with drugs for T2DM, in December 2008, the FDA issued new guidance for all diabetes drugs in development: Manufacturers of diabetes drugs and biologics need to provide evidence that therapy will not increase the risk of CV events More robust and adequate design and data collection are required for Phase 2/3 clinical trials:  New diabetes therapies should not increase CV risk compared with current therapies.  Trials should include patients at higher risk of CV events CV events occurring during clinical trials should be analyzed by independent committees  This includes major events (CV mortality, MI, and stroke) and can also include hospitalization for ACS, urgent revascularization procedures, and other end points EMA. 2012. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500129256&mid=WC0b01ac058009a3dc.

FDA. 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

18

FDA Criteria for Assessing CV Risk

19

Completed and On-going CVOTs of diabetic drugs 2018

2019

LEADER13 (n=9,340)

HARMONY18 (n=9,463)

CREDENCE22 (n=4,401)

TECOS10 (n=14,671)

CANVAS14 (n=10,142)

CARMELINA19 (n=6,980)

PIONEER-623 (n=3,176)

VADT5 (n=1,791)

ELIXA11 (n=6,068)

EXSCEL15 (n=14,752)

DECLARE20 (n=17,160)

REWIND24 (n=9,901)

ACCORD6 (n=10,251)

VADT12 (n=7,637)

SUSTAIN-616 (n=3,297)

VERTIS-CV21 (n=8,237)

CAROLINA25 (n=6,041)

1998

2008-2010

2013

2015

UKPDS-331 (n=3,867)

UKPDS3 10-year follow

SAVOR7 (n=16,492)

EMPA-REG9 (n=7,020)

UKPDS-342 (n=1,704)

ADVANCE4 (n=11,240)

EXAMINE8 (n=5,380)

DEVOTE17 (n=7,637)

: traditional oral drugs or insulin : DPP-4 inhibitors

: SGLT-2 inhibitors

2016-2017

DAPA-HF26 (n=4,695)

: GLP-1 agonists

: On-going trials 1. Lancet 1998; 352: 837–53; 2. Lancet 1998; 352: 854–65; 3. N Engl J Med. 2008 Oct 9;359(15):1577-89.; 4. N Engl J Med. 2008 Jun 12;358(24):2560-72.; 5. N Engl J Med 2009; 360:129-139; 6. N Engl J Med 2008; 358:2545-2559.; 7. N Engl J Med. 2013 Oct 3;369(14):1317-26; 8. N Engl J Med. 2013 Oct 3;369(14):1327-

199,981 patients enrolled;

x 16 ;

35; 9. N Engl J Med 2015;373:2117–2128; 10. N Engl J Med. 2015 Jul 16;373(3):232-42.; 11. N Engl J Med. 2015 Dec 3;373(23):2247-57.; 12. N Engl J Med. 2015 Jun 4;372(23):2197-206.; 13. N Engl J Med. 2016 Jul 28;375(4):311-22.; 14. N Engl J Med. 2017 Aug 17;377(7):644-657.; 15. N Engl J Med. 2017 Sep 28;377(13):1228-1239.; 16. N Engl J Med. 2016 Nov 10;375(19):1834-1844; 17. N Engl J Med. 2017 Aug 24;377(8):723-732.; 18. Lancet. 2018 published online Oct 2. http://dx.doi.org/10.1016/S0140-6736(18)32261-X; 19. Cardiovasc Diabetol. 2018 Mar 14;17(1):39.; 20. Diabetes Obes Metab. 2018 May;20(5):1102-1110.; 21. JACC March 20, 2018 Volume 71, Issue 11; 22. Am J Nephrol. 2017 Dec 13;46(6):462-472.; 23. https://clinicaltrials.gov/ct2/show/NCT02692716 ; 24. Diabetes Obes Metab. 2018 Jan;20(1):42-49.; 25. Diab Vasc Dis Res. 2015 May;12(3):164-74.; 26. https://clinicaltrials.gov/ct2/show/NCT03036124

x3 20

Completed CVOTs: Summary of Outcomes 1998-2008

1.

2008-2018 SAVOR7 EXAMINE8 TECOS10 ELIXA11 EXSCEL15 DEVOTE17 CARMELINA19

EMPA-REG9 LEADER13 CANVAS14 SUSTAIN-616 HARMONY18 DECLARE20

UKPDS-331 ADVANCE4 VADT5 ACCORD6

UKPDS-342

Neutral

Beneficial

Neutral

Beneficial

No Macrovascular benefit with treatment

Macrovascular complications reduced with treatment

Noninferior to placebo or standard of care

Lower rates of CV events vs. placebo or standard of care

Lancet 1998; 352: 837–53; 2. Lancet 1998; 352: 854–65; 3. N Engl J Med. 2008 Oct 9;359(15):1577-89.; 4. N Engl J Med. 2008 Jun 12;358(24):2560-72.; 5. N Engl J Med 2009; 360:129-139; 6. Lancet. 2010 Aug 7;376(9739):419-30.; 7. N Engl J Med. 2013 Oct 3;369(14):1317-26; 8. N Engl J Med. 2013 Oct 3;369(14):1327-35; 9. N Engl J Med 2015;373:2117–2128; 10. N Engl J Med. 2015 Jul 16;373(3):232-42.; 11. N Engl J Med. 2015 Dec 3;373(23):2247-57.; 12. N Engl J Med. 2015 Jun 4;372(23):2197-206.; 13. N Engl J Med. 2016 Jul 28;375(4):311-22.; 14. N Engl J Med. 2017 Aug 17;377(7):644-657.; 15. N Engl J Med. 2017 Sep 28;377(13):1228-1239.; 16. N Engl J Med. 2016 Nov 10;375(19):1834-1844; 17. N Engl J Med. 2017 Aug 24;377(8):723-732.; 18. Lancet. 2018 published online Oct 2. http://dx.doi.org/10.1016/S01406736(18)32261-X; 19. Cardiovasc Diabetol. 2018 Mar 14;17(1):39.; 20. https://www.astrazeneca.com/media-centre/press-releases/2018/farxiga-achieved-a-positive-result-in-the-phase-iii-declare-timi-58-trial-a-large-cardiovascular-outcomes-trial-in-17000-patients-with-type-2-diabetes-

21

How Applicable Might these CVOT Results Be To The General Population of Patients with T2DM?

21% of patients with T2DM had CV presentation

22

CVOT, Cardiovascular Outcome Trial in Type 2 Diabetes Mellitus; T2DM, Type 2 diabetes mellitus A retrospective study was conducted using the Quintiles Electronic Medical Record database. N=1.39 million Iglay K et al. Curr Med Res Opin. 2016 Jul;32(7):1243-52.

Current CV outcome trials of T2DM drugs enrolled most patients with established CVD â&#x20AC;&#x201C; DPP-4 inhibitors % of enrolled patients without established CVD

21.5%

0%

26.0%

43.0%

n=16,492

n=5380

n=14,671

n=6980

CVOT: cardiovascular outcome trial 1. N Engl J Med. 2013 Oct 3;369(14):1317-26. 2. N Engl J Med. 2013 Oct 3;369(14):1327-35. 3. N Engl J Med. 2015 Jul 16;373(3):232-42.; 4. Cardiovasc Diabetol. 2018 Mar 14;17(1):39.; 5. Diab Vasc Dis Res. 2015 May;12(3):16474.

4 DPP-4i all show neutral CV outcome SAVOR-TIMI 531 CVD (78.5%) or CRFs A1c 6.5-12% n=16,492

Saxagliptin

Medium Follow-up 2.1 years

R Placebo

Primary endpoint

Hazard ratio

CV death, Non-fatal MI, or nonfatal stroke

1.0 (95% CI 0.89-1.12) P=0.99

CV death, Non-fatal MI, or nonfatal stroke

0.96 (upper boundary of 1-sided CI 1.16) P=0.315

CV death, non-fatal MI, non-fatal stroke, or unstable angina hospitalization

0.98 (95% CI 0.89-1.08) P=0.99

CV death, Non-fatal MI, or nonfatal stroke

1.02 (95% 0.89-1.17) P=0.73

EXAMINE2 ACS A1c 6.5-11% n=5,380

Alogliptin

Medium Follow-up 1.5 years

R Placebo

TECOS3 CVD (74%) or CRFs A1c 6.5-8% n=14,671

Sitagliptin R Placebo

Medium Follow-up 3.0 years

CARMELINA4 CVD (57%) or CKD A1c 6.5-10% n=6,979

24

Linagliptin R

Placebo

Medium Follow-up 2.2 years

CVD: cardiovascular disease, CRF: cardiovascular risk factor, ACS: acute coronary syndrome, MI: myocardial infarction, CKD: chronic kidney disease 1. Scirica BM et al. N Engl J Med. 2013 Oct 3;369(14):1317-26. 2. White WB et al. N Engl J Med. 2013 Oct 3;369(14):1327-35. 3. Green JB et al. N Engl J Med. 2015 Jul 16;373(3):232-42. 4. Julio Rosenstock et al. 54th Annual Meeting of European Association for the Study of Diabetes (EASD) 2018: Oral Presentation S35.

Current CV outcome trials of T2DM drugs enrolled most patients with established CVD â&#x20AC;&#x201C; GLP-1 receptor agonist % of enrolled patients without established CVD

0%

18.7%

17.0%

26.9%

0%

n=6,068

n=9,340

n=3,297

n=14,752

n=9,463

1. N Engl J Med. 2015 Dec 3;373(23):2247-57. 2. N Engl J Med. 2016 Jul 28;375(4):311-22. 3. N Engl J Med. 2016 Nov 10;375(19):1834-1844. 4. N Engl J Med. 2017 Sep 28;377(13):1228-1239.; 5. Lancet. 2018 published online Oct 2. http://dx.doi.org/10.1016/S0140-6736(18)32261-X

3 GLP-1 RA show positive CV outcome (1) Primary endpoint

ELIXA1 ACS A1c 5.5-11% n=6,068

Lixisenatide Medium Follow-up 2.1 years

R Placebo

CV death, Non-fatal MI, or nonfatal stroke

Hazard ratio 1.02 (95% CI 0.89-1.17) P=0.81

LEADER2 CVD (81.3%) or CRFs A1c ≥7.0% n=9,340

Liraglutide R Placebo

Medium Follow-up 3.8 years

CV death, Non-fatal MI, or nonfatal stroke

0.87 (95% CI 0.78-0.97) P=0.01

CV death, Non-fatal MI, or nonfatal stroke

0.74 (95% CI 0.58-0.95) P=0.02

CV death, Non-fatal MI, or nonfatal stroke

0.91 (95% CI 0.83-1.00) P=0.06

SUSTAIN-63 CVD (83%) or CRFs A1c ≥7.0% n=3,297

Semaglutide Medium Follow-up 2.1 years

R Placebo

EXSCEL4 CVD (73%) or CRFs A1c 6.5-10% n=14,752

26

Exenatide R Placebo

Medium Follow-up 3.2 years

Premature Study Medication Discontinuation: 44%

CVD: cardiovascular disease, CRF: cardiovascular risk factor, ACS: acute coronary syndrome, MI: myocardial infarction 1. Pfeffer MA et al. N Engl J Med. 2015 Dec 3;373(23):2247-57. 2. Marso SP et al. N Engl J Med. 2016 Jul 28;375(4):311-22. 3. Marso SP et al. N Engl J Med. 2016 Nov 10;375(19):1834-1844. 4. N Engl J Med. 2017 Sep 28;377(13):1228-1239.

3 GLP-1 RA show positive CV outcome (2) HARMONY1 CVD (100%) A1c >7% n=9,463

Albiglutide R

Medium Follow-up 1.6 years

Placebo

Primary endpoint

Hazard ratio

CV death, Non-fatal MI, or nonfatal stroke

0.78 (95% CI 0.68-0.90) P=0.0006

CV death, Non-fatal MI, or nonfatal stroke

2018 Aug. Study Completion Not published

CV death, Non-fatal MI, or nonfatal stroke

2018 Sep. Study Completion Not published

REWIND2,3 CVD (31%) or CRFs A1c â&#x2030;¤9.5% n=9,901

Dulaglutide

Mean Follow-up 6.5 years

R Placebo

PIONEER-64,5 CVD (84.6%) or CRFs Type 2 diabetes n=3,183

27

Oral Semaglutide R

Placebo

Medium Follow-up 1.3 years

CVD: cardiovascular disease, CRF: cardiovascular risk factor, MI: myocardial infarction 1. Lancet. 2018 Oct 1. pii: S0140-6736(18)32261-X. 2. Diabetes Obes Metab. 2018 Jan;20(1):42-49. 3. https://clinicaltrials.gov/ct2/show/NCT01394952 4. https://clinicaltrials.gov/ct2/show/NCT02692716 5. Diabetes Obes Metab. 2018 Oct 4. doi: 10.1111/dom.

CVOTs of GLP-1RA

1. Pfeffer MA et al. N Engl J Med. 2015 Dec 3;373(23):2247-57.

2. N Engl J Med. 2017 Sep 28;377(13):1228-1239.

3. Marso SP et al. N Engl J Med. 2016 Jul 28;375(4):311-22.

7. https://www.medscape.com/viewarticle/904373

4. Marso SP et al. N Engl J Med. 2016 Nov 10;375(19):1834-1844 5. Lancet. 2018 Oct 1. pii: S0140-6736(18)32261-X. 6. Diabetes Obes Metab. 2018 Jan;20(1):42-49.

8. https://www.novonordisk.com/media/news-details.2226789.html

ELIXA1

EXSCEL2

LEADER3

SUSTAIN-64

HARMONY5

REWIND6,7

PIONEER-68

Lyxumia

Bydureon

Victoza

Ozempic 台灣未上市

Tanzeum 台灣未上市

Trulicity

未上市

Lixisenatide

Exenatide ER

Liraglutide

Semaglutide

Albiglutide

Dulaglutide

Oral Semaglutide

6,068

14,000

9,340

3,297

9,463

9,901

3,183

2.1

3.2

3.8

2.1

1.6

6.5

1.3

100%

70%

81%

83%

100%

31%

85%

3P MACE

1.02 (4p MACE)

0.91

0.87*

0.74*

0.78*

CV death

0.98

0.88

0.78*

0.98

0.93

Actual Study Completion Date : August 21, 2018

Actual Study Completion Date : September 25, 2018

MI

1.03

0.97

0.88

0.74

0.75*

Top-line News on Nov. 5: ↓ MACE

Stroke

1.12

0.85

0.89

0.61*

0.86

Top-line News on Nov. 23: →← MACE (0.79) ↓ CV death (0.49, p=0.03) →← MI (1.18) →← stoke (0.74)

HHF

0.96

0.94

0.87

1.11

0.85

A1c change (%)

-0.27

-0.53

-0.4

-0.7 / -1.0

-0.52

BW change

-0.7

-1.27

-2.3

-2.9 / -4.3

-0.83

Product

Drug Number Follow-up (yr) CVD(%)

尚未發表 (2019 ADA)

尚未發表

Both SGLT-2i show positive CV outcome P=0.02 P=0.04

0.86 (0.75-0.97) 0.86 (0.74-0.99) 0.87 0.62 (0.49-0.77) 0.85 0.87 0.90 1.24 0.67 (0.52–0.87) 0.65 (0.50–0.85) 0.78 (0.67–0.91) 0.66 (0.55–0.79) 0.87 (0.74–1.01) 0.68 (0.57–0.82) 0.73 (0.67–0.79) albumin 0.62 (0.54–0.72) 0.60 (0.47–0.77) 0.54 (0.40–0.75)

30

1. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 2. Bruce Neal et al. N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925.

EMPA-REG: Doubling of serum creatinine level accompanied by eGFR of ≤45 ml/min/1.73 m2, initiation of renal-replacement therapy, or death from renal disease; CANVAS: 40% reduction in eGFR, renal-replacement therapy, or renal death

DECLARE TIMI: Established CV Disease and Multiple Risk Factor Definitions Multiple Multiple Risk Risk Factors Factors for CV Disease (MRF): (MRF)

Established EstablishedAtherosclerotic AtheroscleroticCV CVDisease Disease (ECVD): (ECVD)

Age ≥55 years (men), ≥60 years (women)

Age ≥40 years

AND ≥1 additional risk factors:

AND ≥1 additional diagnoses:

•Dyslipidemia (≥1 of following)

•Ischemic heart disease (any of following)

 LDL-C >130 mg/dL (>3.36 mmol/L)  On lipid-lowering therapy

•Hypertension (≥1 of following)  BP >140/90 mm Hg at enrolment  On antihypertensive therapy

•Current smoking  ≥5 cigarettes/day for ≥1 year

   

MI PCI CABG ≥50% coronary stenosis in ≥2 coronary arteries

•Cerebrovascular disease (any of following)  Ischemic stroke  Carotid stenting or endarterectomy

•Peripheral artery disease (any of following)  Peripheral arterial stenting or surgical revascularization  Lower extremity amputation as a result of PAD  Symptomatic IC and ABI <0.90 in last 12 mo.

ABI, ankle-brachial index; BP, blood pressure; CABG, coronary artery bypass grafting; CV, cardiovascular; IC, intermittent claudication; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; mo., month; PAD, peripheral artery disease; PCI, percutaneous coronary intervention.

Wiviott SD et al. Supplemental materials. Am Heart J. 2018;200:83-89.

Primary Endpoint â&#x20AC;&#x201C; CV death or HHF

HHF: hospitalization for heart failure

Wiviott SD, Raz I et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389.

AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

HHF (hospitalization for heart failure)

Wiviott SD, Raz I et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389.

AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

Meta-analysis of HF result by eGFR Hospitalization for heart failurestratified by the eGFR levels

P value for risk reduction across subgroups was 0.0073

Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X. doi: 10.1016/S0140-6736(18)32590-X. AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

Primary Endpoint â&#x20AC;&#x201C; MACE

MACE: major adverse cardiovascular events (CV death, MI, or ischemic stroke)

Wiviott SD, Raz I et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389.

AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

Primary MACE Outcome EMPA-REG

CANVAS

3

36

1. Zinman B, et al. N Engl J Med 2015;373:2117â&#x20AC;&#x201C;2128; 2. Bruce Neal et al. N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925.

Meta-analysis of MACE result by ASCVD vs MRF

value for risk PP for interaction reduction across =0.63

subgroups was 0.63

Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X. doi: 10.1016/S0140-6736(18)32590-X. AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

Meta-analysis of MACE result by eGFR MACE(major adverse cardiovascular events) stratified by the eGFR levels

P value for risk reduction across subgroups was 0.23

Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X. doi: 10.1016/S0140-6736(18)32590-X. AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

Meta-analysis of MI result of 3 CVOTs of SGLT2i

Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X. doi: 10.1016/S0140-6736(18)32590-X.

Meta-analysis of MI result by ASCVD vs MRF

Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X. doi: 10.1016/S0140-6736(18)32590-X.

Meta-analysis of Renal result by eGFR Composite of worsening of renal function, end-stage renal disease, or renal death stratified by the eGFR levels

P value for risk reduction across subgroups was 0.0258

Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X. doi: 10.1016/S0140-6736(18)32590-X. AstraZeneca does not recommend the use of dapagliflozin for indication other than T2DM.

A1c(%)1 -0.39

Renal2

HF2

MACE2

-33%

-40%

-18% eGFR<60

-0.54

-44%

-0.69

-56%

-31%

-9%

eGFR 60-90

eGFR >90

1. Traci Mansfield et al. Presented at the 48th Annual Meeting of the EASD, Berlin, Germany, October 2-5, 2012; P754; 2. Zelniker TA et al. Lancet. 2018 Nov 9. pii: S0140-6736(18)32590-X

8 trials : 77,242 patients (5 GLP1-RA & 3 SGLT2i) 42,920 (55.6%) patients in GLP1-RA trials 34,322 (44.4%) patients in SGLT2i trials

Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.

Meta-Analysis of GLP-1 RA and SGLT-2i trials on MACE

13% 14%

Neutral

Neutral

44

Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.

Meta-Analysis of GLP1-RA and SGLT2i trials on hospitalization for heart failure

Neutral

31%

45

Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.

Meta-Analysis of GLP1-RA and SGLT2i trials on broad kidney endpoint including macroalbuminuria New onset macroalbuminuria, sustained doubling of serum creatinine or a 40% decline in eGFR, ESRD, or death of renal cause

18%

38%

46

Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.

Meta-Analysis of GLP1-RA and SGLT2i trials on kidney outcome excluding macroalbuminuria Sustained doubling of serum creatinine or a 40% decline in eGFR, ESRD, or death of renal cause

Neutral

45%

47

Circulation. 2019 Feb 21. doi: 10.1161/CIRCULATIONAHA.118.038868.

Outline • Risk factors, mortality, and CV outcomes in patients with type 2 diabetes • CV outcome trials of diabetic medication • The latest clinical guidelines in 2019 • Conclusion

48

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2019

Diabetes Care 2019;42(Suppl. 1):S90â&#x20AC;&#x201C;S102

CAN-SLK-20190108

Choosing glucose-lowering medication in those with established atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD)

50

Diabetes Care 2018 Oct 4. pii: dci180033. doi: 10.2337/dci18-0033.

This slide includes information for the purpose of scientific medical exchange only. AstraZeneca has no intention to promote its drugs outside of it approved indications.

51

Diabetes Care 2018 Oct 4. pii: dci180033. doi: 10.2337/dci18-0033.

Caveats and Questions No evidence of CVD benefit in those at lower cardiovascular risk The combination of SGLT2-i and GLP-1 RA has not been tested in cardiovascular outcome trials

52 This slide includes information for the purpose of scientific medical exchange only. AstraZeneca has no intention to promote its drugs outside of it approved indications.

53

2019 DAROC Clinical Practice Guidelines for Diabetes Care 8個臨床情境 1. 降低心血管疾病風險 2. 降低心衰竭風險 3. 降低腎臟疾病風險 4. 減少低血糖風險 5. 糖胖症 6. 飯後高血糖 7. 嚴重高血糖 8. 年長, 衰弱, 失能

http://www.endo-dm.org.tw/dia/direct/index.asp?BK_KIND=29&current=2018%E7%B3%96%E5%B0%BF%E7%97%85%E8%87%A8%E5%BA%8A%E7%85%A7%E8%AD%B7%E6%8C%87%E5%BC%95+++++++++++++++++

Outline • Risk factors, mortality, and CV outcomes in patients with type 2 diabetes • CV outcome trials of diabetic medication • The latest clinical guidelines in 2018 • Conclusion

55

Diabetologia. 2013 Apr;56(4):686â&#x20AC;?95.

Diabetes Care. 2016 May;39(5):717â&#x20AC;?25.

Founding Chairman, TIMI Study Group Professor, Harvard Medical School, Cardiovascular Medicine Editor of Harrisonâ&#x20AC;&#x2122;s Principles of Internal Medicine Braunwald's Heart Disease

Eugene Braunwald. Presented at American Heart Association's Scientific Sessions 2018, November 10-12, Chicago, Illinois, USA

Conclusions • Control of 5 risk factors including A1c, BP, LDL, albuminuria, smoking can lower risk of death, MI, stroke, but not HF • Concerns about the CV safety led FDA to mandate that all new glucose-lowering agents must be tested for CV endpoint trials in 2008 • 4 DPP-4i all show neutral CV outcome • 3 of the 5 GLP-1 RA show positive CV outcome (LEADER, SUSTAIN-6, HARMONY) • 3 SGLT-2i show positive CV outcome (EMPA-REG, CANVAS, DECLARE)

• The lasted guideline recommend CV benefit of GLP-1 RA and CV/renal benefit of SGLT-2i for T2DM management

59