ACCP Cardiology PRN Journal Club Announcements Thank you
ACCP Cardiology PRN Journal Club
Announcements • Thank you attending the ACCP Cardiology PRN Journal Club • Thank you if you attended before or have been attending • A PB Works Site has been created that houses our recorded calls, handouts, and Summary/Q&A documents. The link is https: //accpcardsprnjournalclub. pbworks. com/ • If there any suggestions, please let us know.
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes EMPA-REG OUTCOME Michelle Lew, Pharm. D, BCPS PGY 2 Cardiology Resident University of Southern California April 28, 2016 3
Anti-Diabetic Drugs and Cardiovascular Outcomes � Type 2 diabetes mellitus � 3 -fold increase in CV mortality � 2 -fold increase in overall mortality � Benefit of intensive glycemic control on macrovascular outcomes controversial � Since 2008, FDA has required assessment of cardiovascular safety for all new anti-diabetic agents Centers for Disease Control and Prevention, 2011. Sanon S et al, Am J Cardiol, 2012. 4
Anti-Diabetic Drugs and Cardiovascular Outcomes Drug CV Effects Biguanides w Significant reduction in CV events w Reduces LDL; increases HDL Sulfonylureas w May increase risk of CV events w May prevent protective ischemic cardiac preconditioning after MI Meglitinides w May increase ischemic events and LV dysfunction in patients with underlying CAD w No effect on reducing CV outcomes Thiazolidinedones w Increased risk of MI, CHF, and mortality w Possible CHF exacerbation in older patients with underlying CAD DPP-4 inhibitors w Does not increase risk of major CV events w Hospitalization for HF higher with saxagliptin* GLP-1 agonists w Moderate decrease in risk of CVD and CVD-related hospitalizations UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998. The University Group Diabetes Program. Diabetes 1976. Cioffi G, et al. Diabetes Res Clin Pract 2013. Nissen SE, et al. N Engl J Med 2007. Scirica BM, et al. N Engl J Med 2013. Best JH, et al. Diabetes Care 2011. 5
Background: SGLT-2 Inhibitors � Newest class of medications approved for the treatment of type 2 diabetes mellitus �Canagliflozin (Invokana) �Dapagliflozin (Farxiga) �Empagliflozin (Jardiance) 6
Background: SGLT-2 Inhibitors Accessed April 7, 2016. http: //agscientific. com/blog/index. php/2016/01/26/diabetes-2016/ 7
Background: SGLT-2 Inhibitors Mechanism of action: �Blocks glucose reabsorption in the kidney � Associated with: �Weight loss �Reductions in blood pressure without increases in heart rate �Increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) �Urinary tract infections (most common side effect) � 8
EMPA-REG OUTCOME � Study Objective: �Examine the effects of empagliflozin, as compared with placebo, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events 9
Study Design � Randomized, double-blind, placebo-controlled trial in 590 sites in 42 countries Inclusion Criteria Exclusion Criteria w w w w Uncontrolled hyperglycemia >240 mg/d. L w Treatment with systemic steroids w Uncontrolled endocrine disorder except type 2 diabetes w Contraindications to treatment Diagnosis of type 2 diabetes mellitus Drug-naïve to anti-diabetic therapy ≥ 18 years of age BMI ≤ 45 e. GFR ≥ 30 ml/min High cardiovascular risk* 10
High Risk of CV Events � High cardiovascular risk defined as at least one of the following: �History of MI >2 months prior to consent w Evidence of multi-vessel coronary artery disease, in 2+ major coronary arteries, irrespective of revascularization status w Unstable angina >2 months prior to consent w History of stroke (ischemic or hemorrhagic) >2 months prior to consent w Occlusive peripheral artery disease 11
Study Procedures Cardiovasc Diabetol. 2014; 13(102) © 2014 Bio. Med Central, Ltd. 12
Study Outcomes � Primary: Composite endpoint: - Death from cardiovascular causes - Nonfatal myocardial infarction - Nonfatal stroke � Secondary: Composite endpoint: - Primary composite endpoint - Hospitalization for unstable angina 13
Statistical Analysis � Four-step hierarchical-testing strategy for the pooled empagliflozin group vs. placebo group �Noninferiority for the primary outcome �Noninferiority for the secondary outcome �Superiority for the primary outcome �Superiority for the secondary outcome 14
Statistical Analysis � Noninferiority for primary outcome �At least 691 events required to provide a power of at least 90% � Intention-to-treat approach 15
Results � 7028 patients underwent randomization � 97% of patients completed the study � 25. 4% of patients prematurely discontinued a study drug during trial � Median duration follow-up: 2. 6 years 16
Results: Study Demographics Characteristic Placebo (N=2333) Empa 10 mg (N=2345) Empa 25 mg (N=2342) Age - years 63. 2 ± 8. 8 63. 0 ± 8. 6 63. 2 ± 8. 6 Male – no. (%) 1680 (72. 0) 1653 (70. 5) 1683 (71. 9) CV Risk Factor – no. (%) 2307 (98. 9) 2333 (99. 5) 2324 (99. 2) Coronary artery disease 1763 (75. 6) 1782 (76. 0) 1763 (75. 3) Multivessel coronary artery disease 1100 (47. 1) 1078 (46. 0) 1101 (47. 0) History of myocardial infarction 1083 (46. 4) 1107 (47. 2) 1083 (46. 2) CABG 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 disease 238 (10. 2) 258 (11. 0) 240 (10. 2) Cardiac failure 244 (10. 5) 240 (10. 2) 222 (9. 5) 17
Placebo (N=2333) Empa 10 mg (N=2345) Empa 25 mg (N=2342) 8. 08 ± 0. 84 8. 07 ± 0. 86 8. 06 ± 0. 84 Metformin 1734 (74. 3) 1729 (73. 7) 1730 (73. 9) Insulin 1135 (48. 6) 1132 (48. 3) 1120 (47. 8) 52. 0 52. 5 54. 0 Sulfonylurea 992 (42. 5) 985 (42. 0) 1029 (43. 9) DPP 4 -Inhibitors 267 (11. 4) 282 (12. 0) 247 (10. 5) Thiazolidinedione 101 (4. 3) 96 (4. 1) 102 (4. 4) Monotherapy 691 (29. 6) 704 (30. 0) 676 (28. 9) Dual Therapy 1148 (49. 2) 1110 (47. 3) 1149 (49. 1) ACE-i/ARBs 1868 (80. 1) 1896 (80. 9) 1902 (81. 2) Beta-blockers 1498 (64. 2) 1530 (65. 2) 1526 (65. 2) Diuretics 988 (42. 3) 1036 (44. 2) 1011 (43. 2) Calcium channel blockers 788 (33. 8) 781 (33. 3) 748 (31. 9) Aldosterone antagonists 136 (5. 8) 157 (6. 7) 148 (6. 3) Renin Inhibitors 19 (0. 8) 16 (0. 7) 11 (0. 5) Other 191 (8. 2) 193 (8. 2) 190 (8. 1) Characteristic Glycated hemoglobin - % Glucose-lowering therapy – no. (%) Median daily dose - IU Anti-hypertensive therapy – no. (%) 18
Placebo (N=2333) Empa 10 mg (N=2345) Empa 25 mg (N=2342) Lipid-lowering therapy – no. (%) 1864 (79. 9) 1926 (82. 1) 1894 (80. 9) Statins 1773 (76. 0) 1827 (77. 9) 1803 (77. 0) Fibrates 199 (8. 5) 214 (9. 1) 217 (9. 3) Ezetimibe 81 (3. 5) 95 (4. 1) 94 (4. 0) Niacin 35 (1. 5) 56 (2. 4) 35 (1. 5) Other 175 (7. 5) 172 (7. 3) 193 (8. 2) Acetylsalicylic acid 1927 (82. 6) 1939 (82. 7) 1937 (82. 7) Clopidogrel 249 (10. 7) 253 (10. 8) 241 (10. 3 Vitamin K antagonists 156 (6. 7) 141 (6. 0) 125 (5. 3)00 Systolic blood pressure - mm. Hg 135. 8 ± 17. 2 134. 9 ± 16. 8 135. 6 ± 17. 0 Diastolic blood pressure - mm. Hg 76. 8 ± 10. 1 76. 6 ± 9. 8 163. 3 ± 43. 2 Total cholesterol – mg/d. L 161. 9 ± 43. 1 163. 7 ± 45. 2 163. 3 ± 43. 2 LDL – mg/d. L 84. 9 ± 35. 3 86. 3 ± 36. 7 85. 5 ± 35. 2 HDL – mg/d. L 44. 0 ± 11. 3 44. 7 ± 12. 0 44. 5 ± 11. 8 170. 7 ± 121. 2 168. 4 ± 127. 3 172. 6 ± 132. 0 Characteristic Anti-coagulants – no. (%) Triglycerides – mg/d. L 19
Results: Cardiovascular Outcomes 20
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Adverse Events 24
Results: Glycemic Control 25
Author’s Discussion � Decrease in the primary composite outcome was driven by a significant reduction in death from cardiovascular causes, with no significant between -group difference in the risk of myocardial infarction or stroke � Cardiovascular benefits do not appear to be dosedependent 26
Author’s Conclusion � Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin had significantly lower rates of the primary composite cardiovascular outcome and of death from any cause than those in the placebo group when added to standard of care. 27
Critique � Strengths: � Study design and size of study population � Limitations Primary outcome only statistically significant in the pooled empagliflozin group � Adverse effect profile for urinary tract infections not consistent with previous studies with SGLT 2 inhibitors � 28
Implications on Diabetes Management � Class effect or drug effect? � Impact on guidelines? � Metformin vs. SGLT-2 inhibitors as a first-line agent? � Should SGLT-2 inhibitors be used in patients with CV disease and/or heart failure without diabetes? 29
Ongoing Studies � CANVAS Trial � DECLARE-TIMI 58 � Boehringer Ingelheim and Eli Lilly to study empagliflozin for the treatment of chronic heart failure �Enrollment to include heart failure patients with and without diabetes 30
Acknowledgements � Craig Beavers, Pharm. D, FAHA, AACC, BCPS-AQ Cardiology, CACP � UK Healthcare � Carrie Oliphant, Pharm. D, FCCP, BCPS-AQ Cardiology � Methodist University Hospital � Zachary Noel, Pharm. D, BCPS � UK Healthcare � Tien Ng, Pharm. D, FHFSA, FCCP, BCPS-AQ Cardiology � University of Southern California 31
Questions? 32
Thank you for attending! • If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail. com or carrie. Oliphant@mlh. org • Join us next month on May 31 st when Dr. Alex Goncharenko, PGY-2 in Cardiology at the University of Illinois at Chicago, presents the HOPE-3 trial!
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