ACCP Cardiology PRN Journal Club

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EMPA-REG Outcome Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes EMPA-REG Outcome Michelle Lew, PharmD, BCPS PGY2 Cardiology Resident University of Southern California April 28, 2016

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.

Anti-Diabetic Drugs and Cardiovascular Outcomes CV Effects Biguanides Significant reduction in CV events Reduces LDL; increases HDL Sulfonylureas May increase risk of CV events May prevent protective ischemic cardiac preconditioning after MI Meglitinides May increase ischemic events and LV dysfunction in patients with underlying CAD No effect on reducing CV outcomes Thiazolidinedones Increased risk of MI, CHF, and mortality Possible CHF exacerbation in older patients with underlying CAD DPP-4 inhibitors Does not increase risk of major CV events Hospitalization for HF higher with saxagliptin* GLP-1 agonists 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.

Background: SGLT-2 Inhibitors Newest class of medications approved for the treatment of type 2 diabetes mellitus Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance)

Background: SGLT-2 Inhibitors Accessed April 7, 2016. http://agscientific.com/blog/index.php/2016/01/26/diabetes-2016/

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)

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

Study Design Randomized, double-blind, placebo-controlled trial in 590 sites in 42 countries Inclusion Criteria Exclusion Criteria Diagnosis of type 2 diabetes mellitus Drug-naïve to anti-diabetic therapy ≥18 years of age BMI ≤45 eGFR ≥30 ml/min High cardiovascular risk* Uncontrolled hyperglycemia >240 mg/dL Treatment with systemic steroids Uncontrolled endocrine disorder except type 2 diabetes Contraindications to treatment

High Risk of CV Events High cardiovascular risk defined as at least one of the following: History of MI >2 months prior to consent Evidence of multi-vessel coronary artery disease, in 2+ major coronary arteries, irrespective of revascularization status Unstable angina >2 months prior to consent History of stroke (ischemic or hemorrhagic) >2 months prior to consent Occlusive peripheral artery disease

Study Procedures Cardiovasc Diabetol. 2014;13(102) © 2014  BioMed Central, Ltd.

Study Outcomes Primary: Secondary: Composite endpoint: - Death from cardiovascular causes - Nonfatal myocardial infarction - Nonfatal stroke Composite endpoint: - Primary composite endpoint - Hospitalization for unstable angina

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

Statistical Analysis Noninferiority for primary outcome At least 691 events required to provide a power of at least 90% Intention-to-treat approach

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

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) 222 (9.5)

Characteristic Placebo (N=2333) Empa 10 mg (N=2345) Empa 25 mg (N=2342) Glycated hemoglobin - % 8.08 ± 0.84 8.07 ± 0.86 8.06 ± 0.84 Glucose-lowering therapy – no. (%) Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9) Insulin 1135 (48.6) 1132 (48.3) 1120 (47.8) Median daily dose - IU 52.0 52.5 54.0 Sulfonylurea 992 (42.5) 985 (42.0) 1029 (43.9) DPP4-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) Anti-hypertensive therapy – no. (%) 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 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) Other 175 (7.5) 172 (7.3) 193 (8.2) Anti-coagulants – no. (%) 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)1919 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 ± 9.8 163.3 ± 43.2 Total cholesterol – mg/dL 161.9 ± 43.1 163.7 ± 45.2 LDL – mg/dL 84.9 ± 35.3 86.3 ± 36.7 85.5 ± 35.2 HDL – mg/dL 44.0 ± 11.3 44.7 ± 12.0 44.5 ± 11.8 Triglycerides – mg/dL 170.7 ± 121.2 168.4 ± 127.3 172.6 ± 132.0

Results: Cardiovascular Outcomes

Adverse Events

Results: Glycemic Control

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 dose-dependent

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.

Critique Strengths: Limitations Study design and size of study population Primary outcome only statistically significant in the pooled empagliflozin group Adverse effect profile for urinary tract infections not consistent with previous studies with SGLT2 inhibitors

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?

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

Acknowledgements Craig Beavers, PharmD, FAHA, AACC, BCPS-AQ Cardiology, CACP UK Healthcare Carrie Oliphant, PharmD, FCCP, BCPS-AQ Cardiology Methodist University Hospital Zachary Noel, PharmD, BCPS Tien Ng, PharmD, FHFSA, FCCP, BCPS-AQ Cardiology University of Southern California

Questions?

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 31st when Dr. Alex Goncharenko, PGY-2 in Cardiology at the University of Illinois at Chicago, presents the HOPE-3 trial!