UYEN NGUYENPHARMD CANDIDATE 2016

WESTERN NEW ENGLAND UNIVERSITY COLLEGE OF PHARMACY

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2

Diabetes

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.

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.

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.

FDA-Approved SGLT2 Inhibitors for T2DM

Brand name Active ingredient(s)

Invokana canagliflozinInvokamet canagliflozin and

metforminFarxiga dapagliflozinXigduo XR dapagliflozin and

metformin extended-release

Jardiance empagliflozinGlyxambi 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

Review of Drug Class

Advantages DisadvantagesThe 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

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.

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 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.

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.

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.

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.

Inclusion Criteria

Patients who are:≥ 18 years of ageHave T2DMBMI≤ 45eGFR of at least 30mL/min/1.73 m2 BSAHad established cardiovascular diseaseHad received no glucose-lowering agents for

≥12 weeks before randomizationHad HbA1c ≥ 7.0% and ≤ 9.0%

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.

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.

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

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.

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.

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.

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.

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:

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)

Patient Population/Baseline Characteristics

Placebo (N=2333)

Empagliflozin (N=4687)

Systolic BP (mmHg) 135.8±17.2 135.3±16.9Diastolic BP (mmHg) 76.8±10.1 76.6±9.7Total cholesterol (mg/dL)

• LDL• HDL• TG

161.9±43.184.9±35.344.0±11.3

170.7±121.2

163.5±44.285.9±36

44.6±11.9170.5±129.7

eGFR 73.8±21.1 74.2±21.6Urine albumin-to-creatinine ratio (%)

• <30 mg/g• 30 to 300 mg/g• >300mg/g

59.228.911.1

59.528.510.9

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.

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.

Results

Absolute reduction in CV outcomes

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.

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.

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.

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.

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%

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.

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.

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.

Discussion

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

Limitation

Results cannot be extrapolated to patient populations with other clinical characteristics.

Risk-benefit profile was not discussed.

Implication

May prove that the risk of cardiovascular death in patients with T2DM and cardiovascular disease can be modified.

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.