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U Y E N N G U Y E N
P H A R M D C A N D I D A T E 2 0 1 6
W E S T E R N N E W E N G L A N D U N I V E R S I T Y
C O L L E ...
Background
 There are 29.1 mil Americans (9.3% of the
population) with Type 2 Diabetes Mellitus (T2DM) in
20121.
 Remain...
Sodium-Glucose Cotransporter 2 (SGLT2)
Inhibitors
 SGLT2 receptors are expressed almost exlcusively
in the kidney and are...
Sodium-Glucose Cotransporter 2 (SGLT2)
Inhibitors
 Other agents: dapagliflozin, empagliflozin, and
combination products.
...
FDA-Approved SGLT2 Inhibitors for T2DM
Brand name Active ingredient(s)
Invokana canagliflozin
Invokamet canagliflozin and ...
Review of Drug Class
Advantages Disadvantages
The effects is independent of
insulin secretion by the
pancreas.
High cost (...
Empagliflozin (Jardiance®)
 Dosing: initial 10mg po once daily; may increase
to 25mg po once daily4.
 Dose adjustment:
...
Available from: http://media.breitbart.com/media/2015/09/ap_jardiance_ap-photo-wi-640x640.jpg
Zinman B, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med; 2015 5
Background
 The presence of both T2DM and CV disease
increases the risk of death.
 Evidence that glucose-lowering therap...
EMPA-REG OUTCOME TRIAL
 The effects of empagliflozin in addition to standard
care, on cardiovascular morbidity and mortal...
Study Design
 Designed and overseen by steering committee of
academic investigators and employees of
Boehringer Ingelheim...
Study Design
 Locations: 590 sites from 42 countries in North
America (plus Australia and New Zealand), Latin
America, Eu...
Inclusion Criteria
Patients who are:
 ≥ 18 years of age
 Have T2DM
 BMI≤ 45
 eGFR of at least 30mL/min/1.73 m2 BSA
 H...
Definition of High Risk of Cardiovascular Events
(≥1 of the following)
 H/o of MI >2mo prior to informed consent.
 Evide...
Key Exclusion Criteria
Patients who have:
 Uncontrolled hyperglycemia (glucose >240 mg/dL).
 Liver disease (indicated by...
Study Procedures
 2-week, open-label, placebo run-in period with unchanged
background glucose-lowering therapy.
 7020 pa...
Study Procedures
 During first 12 weeks after randomization:
 Background glucose-lowering therapy remained unchanged .
...
Study Outcomes
 Primary outcome: composite of death from
cardiovascular causes, nonfatal MI (excluding silent
MI), or non...
Safety/Adverse Events
 Safety was assessed on the basis of adverse events
occurred during and 7 days after the last dose....
Statistical Analysis
 Statistical model for primary analysis: Cox
proportional- hazards model with study group, age,
sex,...
Statistical Analysis
 Age
 Sex
 Race
 Ethnicity
 Region
 HbA1c
 BMI
 BP
 eGFR
 urine albumin-to
creatinine ratio...
Patient Population/Baseline Characteristics
 At baseline, demographic and clinical characteristics
are well-balanced betw...
Patient Population/Baseline Characteristics
Placebo
(N=2333)
Empagliflozin
(N=4687)
Systolic BP (mmHg) 135.8±17.2 135.3±16...
Results
 Overall, 97% of patients completed the study, 25.4%
prematurely discontinued the study drug.
 Reasons for prema...
 Primary outcome: statistically significant lower risk of
death in study drug group-HR: 0.86; 95.02% CI:
0.74-0.99; P <0....
Results
 Absolute reduction in CV outcomes
Results- Secondary Outcomes
• Empaglifozin group
showed statically
significant lower risk
of death from CV
causes, death f...
Results
 No statistically significant differences in primary and
secondary outcomes for the 10-mg and 25-mg
groups versus...
Results
 Glycemic control after 12 weeks
 Reduction of 0.54% points (95% CI, -0.58 to -0.49) in 10mg
group.
 Reduction ...
Results
 39 patients (41 in the 10-mg group and 38 in the 25-
mg group) would need to be treated during a 3-year
period t...
Results
 Similar side effect profile between the empagliflozin
group and placebo group.
 Genital infection was reported ...
Authors’ Conclusions
 Patients with T2DM at high risk for cardiovascular
events who received empagliflozin had significan...
Ongoing Study
 CANVAS-Canagliflozin cardiovascular
assessment study: Phase III randomized,
multicenter, double blind, pla...
Ongoing Study
 Multicenter trial to evaluate the effect of
dapagliflozin on the incidence of
cardiovascular events (DECLA...
Discussion
Strengths/Weaknesses
 Strengths
 Sample size
 Study design
 Appropriate statistical
analysis
 Baseline characteristic...
Limitation
 Results cannot be extrapolated to patient
populations with other clinical characteristics.
 Risk-benefit pro...
Implication
 May prove that the risk of cardiovascular death in
patients with T2DM and cardiovascular disease can
be modi...
References
1. Fast facts-data and statistics about diabetes [Internet]. Alexandria, VA: American
Diabetes Association. Ava...
Empagliflozin and Cardiovascular Outcomes
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Empagliflozin and Cardiovascular Outcomes

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Empagliflozin and Cardiovascular Outcomes

  1. 1. U Y E N N G U Y E N P H A R M D C A N D I D A T E 2 0 1 6 W E S T E R N N E W E N G L A N D U N I V E R S I T Y C O L L E G E O F P H A R M A C Y Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
  2. 2. Background  There are 29.1 mil Americans (9.3% of the population) with Type 2 Diabetes Mellitus (T2DM) in 20121.  Remains the 7th leading cause of mortality in the United States in 20101.  Total costs of diagnosed DM is $245 billion in 2012 ($176 billion for direct medical costs and $69 billion in reduced productivity)1.  Hospitalization rates for MI and stroke were 1.8 times and 1.5 times, respectively, higher among adults with DM than those without.
  3. 3. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors  SGLT2 receptors are expressed almost exlcusively in the kidney and are responsible for the majority of glucose reabsorption2.  Inhibition of SGLT2 can decrease plasma glucose by increasing urinary glucose excretion2.  First agent, canagliflozin (Invokana®) became available on the US market May, 2013.
  4. 4. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors  Other agents: dapagliflozin, empagliflozin, and combination products.  Both canagliflozin and dapagliflozin are on the VA’s non-formulary.  Formulary status of empagliflozin is pending.  The drug monograph is available on PBM Intranet.
  5. 5. FDA-Approved SGLT2 Inhibitors for T2DM Brand name Active ingredient(s) Invokana canagliflozin Invokamet canagliflozin and metformin Farxiga dapagliflozin Xigduo XR dapagliflozin and metformin extended-release Jardiance empagliflozin Glyxambi empagliflozin and linagliptin Synjardy empagliflozin and metformin List of fda-approved sglt2 inhibitors for type 2 diabetes. Available from http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm3
  6. 6. Review of Drug Class Advantages Disadvantages The effects is independent of insulin secretion by the pancreas. High cost (approx. $200+/month) Mean reduction of HbA1c ≤1% Increased risks of UTIs, genital mycotic infections, osmotic diuresis, hypotension Weight loss FDA-warning about DKA (12/4/15) that requires surveillance for 5 years for all SGLT2 inhibitors3 Reduction in BP
  7. 7. Empagliflozin (Jardiance®)  Dosing: initial 10mg po once daily; may increase to 25mg po once daily4.  Dose adjustment:  Persistent eGFR <45: d/c therapy.  eGFR <30: use is contraindicated.  ESRD, dialysis: use is contraindicated.  Common Adverse Events: hypoglycemia, UTI, increased LDL cholesterol (5-7%), dyslipidemia, increased hematocrit (3-4%), increased risk of DKA4.
  8. 8. Available from: http://media.breitbart.com/media/2015/09/ap_jardiance_ap-photo-wi-640x640.jpg
  9. 9. Zinman B, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med; 2015 5
  10. 10. Background  The presence of both T2DM and CV disease increases the risk of death.  Evidence that glucose-lowering therapy reduces the rates of CV events and death has not been convincingly shown.  There is concern that intensive glucose lowering or the use of specific glucose-lowering drugs may be associated with adverse CV outcomes.  It is necessary to establish the CV safety benefits of glucose-lowering agents.
  11. 11. EMPA-REG OUTCOME TRIAL  The effects of empagliflozin in addition to standard care, on cardiovascular morbidity and mortality in patients with T2DM at high cardiovascular risk are not known.  Hypothesis: to demonstrate noninferiority for the primary outcome with empagliflozin versus placebo with a margin of 1.3 for hazard ratio.
  12. 12. Study Design  Designed and overseen by steering committee of academic investigators and employees of Boehringer Ingelheim.  Phase III, multicenter, international, randomized, double-blind, placebo-controlled trial.  Enrollment: September 2010 to April 2013.
  13. 13. Study Design  Locations: 590 sites from 42 countries in North America (plus Australia and New Zealand), Latin America, Europe, Africa, and Asia.  Trial continued until an adjudicated primary outcome event had occurred in at least 691 patients.
  14. 14. Inclusion Criteria Patients who are:  ≥ 18 years of age  Have T2DM  BMI≤ 45  eGFR of at least 30mL/min/1.73 m2 BSA  Had established cardiovascular disease  Had received no glucose-lowering agents for ≥12 weeks before randomization  Had HbA1c ≥ 7.0% and ≤ 9.0%
  15. 15. Definition of High Risk of Cardiovascular Events (≥1 of the following)  H/o of MI >2mo prior to informed consent.  Evidence of multi-vessel CAD i.e. presence of significant stenosis, prev revascularization, and/or combination of the above.  Evidence of single-vessel CAD: ischemia, hospital discharge for unstable angina ≤12 mo prior to consent.  H/o stroke >2 mo prior to consent.  Occlusive PAD: limb angioplasty, stenting, bypass/amputation d/t circulatory insufficiency; significant peripheral artery stenosis; ankle brachial index <0.9 in ≥ 1 ankle.
  16. 16. Key Exclusion Criteria Patients who have:  Uncontrolled hyperglycemia (glucose >240 mg/dL).  Liver disease (indicated by AST, ALT or alk phosphatase >3x ULN).  Planned cardiac surgery or angioplasty within 3 months.  eGFR <30mL/min/1.73m2.  Contraindications to background therapy according to local label.  Any uncontrolled endocrine disorder except T2DM.  Pre-menopausal women.
  17. 17. Study Procedures  2-week, open-label, placebo run-in period with unchanged background glucose-lowering therapy.  7020 patients randomly assigned in a 1:1:1 ratio to different groups:  Placebo N=2333  Empagliflozin N= 4687  10mg once daily N=2345  25mg once daily N=2342  Blocked randomization was stratified according to:  HbA1c at screening (< 8.5% or ≥8.5%)  BMI (<30 or ≥30)  Renal function (eGFR: 30-59 mL, 60-89 mL or ≥90 mL/min/1.73m2)  Geographic region
  18. 18. Study Procedures  During first 12 weeks after randomization:  Background glucose-lowering therapy remained unchanged .  Intensification of therapy, dose reduction or discontinuation of background medication were allowed if clinically indicated.  After week 12:  Investigators were encouraged to adjust glucose-lowering therapy, and treat other CV risk factors at their discretion to achieve best available standard of care according to local guidelines.  Follow-up visits: at week 4, 8, 12, 16, 28, 40 and 52 after randomization and 30 days after completion of study.
  19. 19. Study Outcomes  Primary outcome: composite of death from cardiovascular causes, nonfatal MI (excluding silent MI), or non fatal stroke.  Key secondary outcome: composite of the primary outcome plus hospitalization for unstable angina.
  20. 20. Safety/Adverse Events  Safety was assessed on the basis of adverse events occurred during and 7 days after the last dose.  Key adverse events are:  Hypoglycemic events (plasma glucose ≤70mg/dL or events requiring assistance).  Side effects: UTI, genital infection, volume depletion, acute renal failure, bone fracture, DKA, and thromboembolic events.
  21. 21. Statistical Analysis  Statistical model for primary analysis: Cox proportional- hazards model with study group, age, sex, baseline BMI, baseline HbA1c, baseline eGFR, and geographic location as factors.  A two-sided P value of 0.0498 was considered to indicate statistically significance.  Modified ITT was used as primary analysis among patients who had received at least one dose of study drug.
  22. 22. Statistical Analysis  Age  Sex  Race  Ethnicity  Region  HbA1c  BMI  BP  eGFR  urine albumin-to creatinine ratio  cardiovascular risk factors  use of glucose-lowering medication  use of statins/ezetimibe  use of anti-hypertensive therapy  use of acetylsalicylic acid. • Kaplan-Meier estimates were used to calculate cumulative incidence for death from any cause. • Subgroup analyses were performed in subgroups by baseline:
  23. 23. Patient Population/Baseline Characteristics  At baseline, demographic and clinical characteristics are well-balanced between placebo and empagliflozin groups:  Median age is 63.2  >70% are male and Caucasian  Average HbA1c is 8.08%  Over 50% of patients have T2DM for >10 years  Over 95% have CV risk factor (i.e: existing CAD, h/o MI, stroke, PAD, cardiac failure…).  90% are on anti-hypertensive therapy (ACE/ARBs > 80%).  About 80% are on lipid-lowering therapy (>70% on statins)  >88% on anti-coagulants (~ 82.6% on acetylsalicylic acid)
  24. 24. Patient Population/Baseline Characteristics Placebo (N=2333) Empagliflozin (N=4687) Systolic BP (mmHg) 135.8±17.2 135.3±16.9 Diastolic BP (mmHg) 76.8±10.1 76.6±9.7 Total cholesterol (mg/dL) • LDL • HDL • TG 161.9±43.1 84.9±35.3 44.0±11.3 170.7±121.2 163.5±44.2 85.9±36 44.6±11.9 170.5±129.7 eGFR 73.8±21.1 74.2±21.6 Urine albumin-to-creatinine ratio (%) • <30 mg/g • 30 to 300 mg/g • >300mg/g 59.2 28.9 11.1 59.5 28.5 10.9
  25. 25. Results  Overall, 97% of patients completed the study, 25.4% prematurely discontinued the study drug.  Reasons for premature discontinuation:  Adverse event  Refusal to continue, not due to adverse event  Non-compliance  Lost to f/u  Lack of efficacy  Other  Final status was available for 99.2% of all patients.  Median duration of treatment: 2.6 years.  Median observation time: 3.1 years.
  26. 26.  Primary outcome: statistically significant lower risk of death in study drug group-HR: 0.86; 95.02% CI: 0.74-0.99; P <0.001 for noninferiority and P=0.04 for superiority.  Key secondary outcome: statistically insignificant between the two groups-HR: 0.89, 95%CI: 0.78-1.01; P<0.001 for noninferiority and P=0.08 for superiority.
  27. 27. Results  Absolute reduction in CV outcomes
  28. 28. Results- Secondary Outcomes • Empaglifozin group showed statically significant lower risk of death from CV causes, death from any cause, and hospitalization for HF; for HF or death from CV causes excluding fatal stroke than in the placebo group. • No significant between-group differences in the occurrence of MI or stroke.
  29. 29. Results  No statistically significant differences in primary and secondary outcomes for the 10-mg and 25-mg groups versus placebo.  HR 0.85 (95% CI, 0.72-1.01; P=0.07) for the 10mg.  HR 0.86 (95% CI, 0.73-1.02; P=0.09) for the 25mg.  In subgroup analyses:  Consistent benefit of empagliflozin versus placebo on death from CV causes across all subgroups.  Some heterogeneity for the primary outcome in age, and HbA1c subgroups.
  30. 30. Results  Glycemic control after 12 weeks  Reduction of 0.54% points (95% CI, -0.58 to -0.49) in 10mg group.  Reduction of 0.60% points (95%CI, -0.64 to -0.55) in 25mg group.  Cardiovascular risk factors  Empagliflozin was associated with small reductions in weight, waist circumference, uric acid level, and BP.  Small increase in LDL and HDL cholesterol observed in the study drug group.
  31. 31. Results  39 patients (41 in the 10-mg group and 38 in the 25- mg group) would need to be treated during a 3-year period to prevent 1 death.  Many patients did not reach their glycemic targets  At week 206, adjusted mean A1c for empagliflozin pooled group is 7.81% and 8.16% for placebo group.
  32. 32. Results  Similar side effect profile between the empagliflozin group and placebo group.  Genital infection was reported in higher percentage of patients in study drug group.  Urosepsis was reported in 0.4% patients in empagliflozin versus 0.1% in placebo group.  No relevant changes in electrolytes between the groups.  Hematocrit values were higher in empagliflozin groups than in placebo group:  Change from baseline in 10mg group: 4.8±5.5%  25mg group: 5.0 ±5.3%  Placebo: 0.9 ±4.7%
  33. 33. Authors’ Conclusions  Patients with T2DM 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 did those in the placebo group when the study drugs were added to standard care.
  34. 34. Ongoing Study  CANVAS-Canagliflozin cardiovascular assessment study: Phase III randomized, multicenter, double blind, placebo-controlled study- Expected to conclude in 2017.  Purpose: to assess canagliflozin in the treatment of patients with T2DM with regard to cardiovascular (CV) risk for major adverse cardiac events (MACE). Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin6.
  35. 35. Ongoing Study  Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58)- randomized, double blind study- Expected to conclude in 2019.  Purpose: To determine if dapagliflozin when added to a patients current anti-diabetes therapy is effective in reducing cardiovascular events such as myocardial infarction (MI) (heart attack), ischemic stroke, and cardiovascular (CV) related death, compared with placebo (inactive study medication)7.
  36. 36. Discussion
  37. 37. Strengths/Weaknesses  Strengths  Sample size  Study design  Appropriate statistical analysis  Baseline characteristics are similar among all patients.  Similar use of medications to manage other health conditions  Weaknesses  Study duration  Majority are male, and Caucasian  All with existing CVD risk factors  Not adequate information available for adverse events of the study drug  Many patients did not reach their glycemic targets
  38. 38. Limitation  Results cannot be extrapolated to patient populations with other clinical characteristics.  Risk-benefit profile was not discussed.
  39. 39. Implication  May prove that the risk of cardiovascular death in patients with T2DM and cardiovascular disease can be modified.
  40. 40. References 1. Fast facts-data and statistics about diabetes [Internet]. Alexandria, VA: American Diabetes Association. Available from: https://professional.diabetes.org/facts. 2. Andrianesis V, Doupis J. The role of kidney in glucose homeostasis- sglt2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol. 2013; 6(5): 519- 539. 3. Fda drug safety communication: fda revises labels of sglt2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections [Internet]. Silver Spring (MD): US Food and Drug Administration; 2015 [cited 2015 Dec 9]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. 4. Empagliflozin. In: Lexi-Drugs [database on the Internet].Hudson (OH): Lexi-Comp, Inc.; 2007 [cited 2015 Dec 9]. 5. Bernad Z, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117-2128. 6. Canvas-canagliflozin cardiovascular assessment study. Bethesda, MD: US National Institutes of Health. Available from: https://clinicaltrials.gov/show/NCT01032629. 7. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (declare-timi58). Bethesda, MD: US National Institutes of Health. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534?term=declare+timi&rank=1.

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