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