Example Journal Club

Sandra R. Bai, PharmD

PGY1 Regulatory Pharmaceutical Fellow in Drug Information
Purdue University|Janssen Scientific Affairs, LLC|FDA
October 12, 2016

Please Note:
O There are many ways to present a journal club
O Overview + Critique
O Critique only

O You may not have all the information that I will

present
O Your assignments will be graded based on
appropriateness and support of your
reasoning
O Critiquing journal articles becomes easier with
time and practice

Overview of Diabetes

Epidemiology

Centers for Disease Control and Prevention. Diabetes 2014 Report Card. Available at
http://www.cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf. Accessed October 11 th, 2016.

Epidemiology
O 21 million Americans with diagnosed

diabetes in 2014
O 8.1 million people undiagnosed
O Mean/median age at diagnosis ~54 yoa
O 90-95% of diabetes cases are T2DM

O Risk factors include: older age, obesity,

family history, history of gestational

diabetes, impaired glucose metabolism,
physical inactivity, and race/ethnicity
Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes
and prediabetes in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control
and Prevention, 2014

Epidemiology

Centers for Disease Control and Prevention. Diabetes 2014 Report Card. Available at
http://www.cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf. Accessed October 11 th, 2016.

Complications Associated
with Diabetes
O Neuropathy, limb amputations
O Nephropathy, kidney failure

O Serious infections
O Glaucoma, cataracts, blindness
O Hypertension
O Heart Disease
O Stroke
O Diabetic ketoacidosis

Type 2 Diabetes Mellitus

(T2DM) Management
O Goal HbA1c < 7% for many nonpregnant adults per

ADA guidelines
O 6.5% for most nonpregnant adults per AACE
guidelines
O Diabetes self-management education (DSME)
O Weight loss
O Diet
O Physical inactivity
O Smoking cessation
O Immunizations
O Preventative care: eye and foot exams, kidney care

American Diabetes
Association

American Association of
Clinical
Endocrinologists

T2DM Management

Glycemic Goals

Diagnosis

(ADA)

(AACE)

A1C

6.5%

FPG

126 mg/dL

2-hr glucose (OGTT)

200 mg/dL

Hyperglycemic crisis

Sx of hyperglycemia + 200 mg/dL

A1c

<7.0%

<6.5%

Pre-prandial glucose

70-130 mg/dL

<110 mg/dL

Post-prandial glucose

<180 mg/dL

<140 mg/dL

Initial pharmacologic
intervention
Add 2nd oral agent if:

Other

Metformin
A1c not controlled (3
months) with max dose
monotherapy

A1c >6.5% in 3
months

Weight loss
Physical Activity

American Diabetes Association. Standard of medical care in diabetes2015. Diabetes Care 2015;38:S1-S93.
Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists comprehensive diabetes management algorithm 2013 consensus
statementexecutive summary. Endocr Pract 2013; 19: 536-57.

American Diabetes Association. Standard of medical care in diabetes2015. Diabetes Care 2015;38:S1-S93.

O Approved August 01, 2014

O Mechanism of action: SGLT-2 inhibitor
O A1c lowering ~ 0.5-1%
O FDA approved indication: Treatment of type

2 diabetes mellitus as an adjunct to diet and

exercise to improve glycemic control
O Dose: 10 mg once daily initially, may
increase to 25 mg once daily
O Price: 10 mg or 25 mg (30): $470.08
Empagliflozin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. Accessed October 12, 2016.

O Common adverse events

O Endocrine/Metabolism

O Genitourinary infections
O Nasopharyngitis
O Hypoglycemia (when combined with other

anti-diabetic agents that cause hypoglycemia)

O Pregnancy category C
O Other SGLT-2 inhibitors
O Dapagliflozin
O Canagliflozin
Empagliflozin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. Accessed October 12, 2016.

O Approved May 02, 2011

O Mechanism of action: dipeptidyl peptidase-4

O
O

O
O

(DPP-4) inhibitor
A1c lowering ~ 0.5-1%
FDA approved indication: Treatment of type
2 diabetes mellitus as an adjunct to diet and
exercise to improve glycemic control
Dose: 5 mg once daily
Price: 5 mg(30): $428.51

Linagliptin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. Accessed October 12, 2016.

O Common adverse events

O Headache

O Endocrine/Metabolism
O Hypoglycemia (when combined with other

anti-diabetic agents that cause hypoglycemia)

O Pregnancy category B
O Other DPP-4 inhibitors
O Sitagliptin
O Saxagliptin
O Alogliptin
Linagliptin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. Accessed October 12, 2016.

Previous studies
Trial Citation

Treatment

Result

DeFronzo RA, Lewin A, Patel

S, Liu D, Kaste R, Woerle HJ,
Broedl UC. Combination of
empagliflozin and linagliptin
as second-line therapy in
subjects with type 2
diabetes inadequately
controlled on metformin.
Diabetes Care 2015
Mar;38(3):384-93.

Add on to metformin:
Empagliflozin 25
mg/linagliptin 5 mg
Empagliflozin 10
mg/linagliptin 5 mg
Empagliflozin 25 mg
Empagliflozin 10 mg
Linagliptin 5 mg

Reduction in HBA1c at week 24:

Empagliflozin 25 mg/linagliptin 5 mg
vs. empagliflozin 25 mg: -0.58 (0.75,-0.41) p<0.001
Empagliflozin 25 mg/linagliptin 5 mg
vs. linagliptin 5 mg: -0.5% (-0.67, 0.32) p<0.001
Empagliflozin/linagliptin 10 mg/5 mg
vs. empagliflozin 10 mg: -0.42% (0.59,-0.25) p<0.001
Empagliflozin/linagliptin 10 mg/5mg
vs. linagliptin 5 mg: -0.39 (-0.56,0.21) p<0.001

Funded by Boehringer Ingelheim and Eli Lilly and Company

Study Objective: To evaluate the efficacy and safety of
empagliflozin/linagliptin in subjects with type 2 diabetes

iClicker Question #1
O Which of the following is/are not found in

the methods section of an article?

O A. Study Design
O B. Baseline Characteristics
O C. Interventions
O D. Statistical Analysis

METHODS

Study Design
Phase III, randomized, double-blind, parallel-group study

Inclusion/Exclusion Criteria
Inclusion:
18 years with type 2
diabetes
BMI 45 kg/m2
A1C >7% to 10.5% at
screening despite a diet
and exercise regimen
No treatment with oral
antidiabetes therapy, GLP1 analog, or insulin for 12
weeks prior to
randomization

Exclusion:
Uncontrolled hyperglycemia (> 240
mg/dL after an overnight fast during
the placebo run-in)
eGFR <60 mL/min/1.73 m2
Acute coronary syndrome, stroke, or
transient ischemia attack within 3
months prior to consent
Bariatric surgery in the last 2 years
Treatment with antiobesity drugs
within 3 months prior to consent

iClicker Question #2
O What type of endpoint is the primary

endpoint of Article #2?

O A. Surrogate endpoint
O B. Clinical endpoint
O C. Composite endpoint
O D. Co-primary endpoint

Endpoints
Primary endpoint:
O Change from baseline in HbA1c at week 24
Secondary endpoints (at week 24)
O Change from baseline in FPG
O Change from baseline weight
O Proportion of subjects with HbA1c<7%
Exploratory endpoints:
O Changes from baseline in HbA1c at week 24 in subgroups
of patients with HbA1 8.5% or <8.5%
O Changes from baseline in HbA1, FPG, weight, systolic and
diastolic BP, and proportion of subjects with HbA1c<7% (at
52 weeks)

Interventions
O Randomized 1:1:1:1:1

Statistical Analysis
O Efficacy analyses: modified intent to treat
O Full analysis set:
O one dose of study drug
O Baseline HBA1c
O on-treatment HBA1c

O Safety analyses
O Treated set
O one dose of study drug

Results

Baseline Characteristics

Primary endpoint

Subgroup analysis of primary endpoint

Secondary endpoints

Safety

Authors Conclusion
O Combination therapy with empagliflozin/linagliptin

had significantly different reductions from baseline

HBA1c versus linagliptin 5 mg and empagliflozin 10
mg but not versus empagliflozin 25 mg
O Initial combination of empagliflozin/linagliptin may

provide a treatment option for patients with type 2

diabetes who are intolerant to metformin and/or have
marked hyperglycemia, without the side effects of
weight gain or increased risk of hypoglycemia

Critique

Journal
O Diabetes Care

O International, peer reviewed, medical journal

O Impact factor-2014: 8.42

Authors
O Lewin A
O Founder and medical director of the National Research

Institute
O Serves as a associate professor of medicine at the
UCLA school of medicine
O >60 publications focusing on HTN, diabetes, and lipid
metabolism
O Defronzo RA
O Serves on the scientific advisory board or Boehringer
Ingelheim
O Patel S, Liu D, Kaste R, Woerle HJ, and Broedl UC are
Boehringer Ingelheim employees

Study Subjects
O
O
O
O
O
O
O

O
O
O
O

Baseline characteristics variable between treatment groups

Predominately white (69.9-77.6%) and minority populations were not well represented
A1c (7.99-8.05%) - may not be representative of most patients with type 2 DM with no
background antidiabetic treatment
FPG (152.8-160.3) most patients with diabetes will have higher FPG
Average age = 54 yoa - average age of patients with type 2 diabetes
Weight/BMI = 86.7-89.5/BMI 31 patients with diabetes are frequently overweight/obese
Average length of diabetes = Most patients within 5 years of diagnosis (likely to already be
on medication therapy)
SBP/DBP (~130/80mmHg) hypertension is a common comorbidity for diabetes; however,
it may not be as well controlled in many patients with diabetes
Excluded patients with eGFR <60 mL/min despite ability to use empagliflozin/linagliptin with
eGFR 45 mL/min
Minimal information on background medications
No information about why patients were excluded from patients screened

Study Design
O

Multicenter, multinational increases generalizability and external validity

O

O
O
O
O
O
O

O
O
O
O
O
O
O

However, did not specify where centers were

Randomization and blinding were appropriate

Clinical trial design is appropriate to establish efficacy of FDC vs. individual components
Clinical trial design not appropriate to assess efficacy of high dose FDC and low dose FDC
Sufficient sample size in each group for 89% power to detect a 0.5% difference in primary endpoint.
No breakdown of why patients were deemed ineligible once screened
Randomization and blinding generally appropriate and stratification was appropriate
Diet and exercise not addressed may be confounding variable
Follow-up was conducted by investigators at weeks 6,12,18,24,32,40, and 52 and appropriate to assess
safety and efficacy
No antidiabetes treatment for 12 weeks prior to randomization appropriate to assess drug-nave A1c
Rescue criteria appropriate precautions to consider for patients who become too hyperglycemic or
hypoglycemic
Appropriate HbA1c cutoff of 10.5% at screening due to guideline recommendations to consider initiating
insulin at this point
Dosing of medications were appropriate
Duration was appropriate (FDA guidances)

Endpoints
O Primary endpoint was appropriate and meaningful
O HbA1c is a surrogate endpoint
O Appropriate measure of diabetes control based on

FDA guidance and ADA/AACE treatment guidelines

O Secondary endpoints were appropriate and

meaningful
O FPG, body weight, and achievement of A1c <7%
O Relevant based on factors associated with diabetes
O Followed till 52 weeks (exploratory)

Results
Primary endpoint:
O Empagliflozin/linagliptin 25/5 mg vs. empagliflozin 25 mg: -0.14 (-0.33 to
0.06) p=0.179
O Empagliflozin/linagliptin 25/5 mg vs. linagliptin 5 mg: -0.41 (-0.61 to -0.22)
p<0.001
O Empagliflozin/linagliptin 10/5 mg vs. empagliflozin 10 mg: -0.41 (-0.61 to 0.21) p<0.001
O Empagliflozin/linagliptin 10/5 mg vs. linagliptin 5 mg: -0.57 (-0.76 to -0.37)
p<0.001
O Secondary endpoint:
O FPG: statistically significant decrease in FPG with combination therapy vs.
linagliptin but not empagliflozin (~23 mg/dL)
O Weight: statistically significant decrease in weight with low dose FDC vs.
linagliptin (~2 kg loss)
O Achieving <7% HBA1c : statistically significant increase in patients achieving
HBA1c <7% except between high dose FDC and empagliflozin 25 mg (OR 3 or 4)
O

iClicker Question #3
O When attempting to determine clinical relevance

of points mentioned in Article #2, which of the

following is not an appropriate resource to
consult?
O A. ADA clinical practice guidelines for diabetes
O B. FDA Guidance for Industry: Developing Drugs

and Therapeutic Biologics for Treatment and

Prevention
O C. Patients Like Me-Diabetes forum
O D. AACE clinical practice guidelines for diabetes

Study Strengths
O Stratification by region, HbA1c,and eGFR at screening appropriate to
O
O

O
O
O
O

reduce sampling error

Randomized, double-blind, parallel-group confounding variables
and bias
Primary endpoint appropriate as it is similar to treatment goals
defined by treatment guidelines and also recommended in FDA
guidance
Multinational, multicenter design increased external validity
Used modified intent-to-treat analysis, which provides a conservative
estimate of efficacy and external validity (also in FDA standard)
Use of MedDRA terms for adverse events increases internal validity
of ADR data collection
Excluded patients with recent bariatric surgery or treatment with antiobesity drugs to increase internal validity of weight gain endpoint

Study Limitations
O No description of diet and exercise-potential confounding
O
O
O

O
O

variable
Baseline A1c/FPG were slightly different between armspotential confounding variable
Majority of patients were white (not representative of high risk
patient populations)- reduces external validity
No details about why patients were excluded from the triallimits external validity
Study was not designed to compare efficacy between the two
combination drug dosing groups
Study was not designed to compare efficacy of low dose FDC
and empagliflozin 25 mg

Generalizability of Results
O Empagliflozin/linagliptin combination

therapy is effective in lowering HbA1c in

patients with type 2 diabetes not on any
other antidiabetic therapy
O Results of this trial can be generalized to
obese, white patients, without renal
dysfunction, a HbA1c ~ 8%, with well
controlled BP, within 5 years of diagnosis

Conclusion/Impact on
Practice
O Glyxambi was approved by the FDA on 02/02/2015 as an

adjunct to diet and exercise to improve glycemic control in adults

with type 2 diabetes
O Launched on 03/23/2015
O Initial dose of 10/5 mg
O Only SGLT-2/DPP-4 inhibitor combination available
O No guideline update
O 10-5 mg or 25-5 mg (30): $609.98
O Patients with metformin intolerance may benefit by initiating a
SGLT-2/DPP-4 inhibitor combination therapy over individual
components with low risk of hypoglycemia
O Jardiance commercial

In Class Discussion

Scenario #1
You are a pharmacist in a primary care office with
physicians. Your medical director asks you if the
practice should begin prescribing Glyxambi as initial
treatment in patients newly diagnosed with diabetes
instead of metformin. After analyzing article #2 how
will you present the information to the doctors in your
practice to give them a balanced view of the trial
results? Which patient factors should they consider
when determining if a patient is a good candidate for
initial treatment with Glyxambi?

Scenario #2
You are a pharmacist in a diabetes ambulatory clinic and have a patient MB
diagnosed with type 2 diabetes one year ago. MB is a 34 YO white female with an
A1C of 8.5%. You have tried controlling her blood glucose with metformin for the past
year but have not been able to get her A1c lower than 8%. You are trying to decide
which medication to initiate for MB to take in addition to metformin. You know there
are many options for combination therapy but are worried the patient is at a higher
risk for hypoglycemia due to her tendency to skip meals. Based on information from
article #2, would Glyxambi be a good option in this patient? Please explain why or
why not.
O PMH: hypertension, hyperlipidemia, asthma, and a ten pack year smoking history
O MBs current medications: metformin 1000 mg by mouth twice daily, lisinopril
10mg by mouth daily, Lipitor 20mg by mouth daily, Advair 250/50 1 oral
inhalation twice daily, and Yaz 1 tablet by mouth daily.

Scenario #3
You are an industry representative that has been
asked to speak to a group of doctors and nurses at a
local primary care physicians office. The office has a
high number of patients with type 2 diabetes and
has shown an interest in using your new medication.
How would you present the information from article
#2 to tell the doctors and nurses about this new
breakthrough first in class medication? Are there any
results of the study you would avoid speaking about?

Scenario #4

Scenario #5
You are a pharmacist working for an insurance
company that is holding a pharmacy &
therapeutics (P&T) meeting to determine
which new drugs should be put on their
formulary. During the meeting, the topic of
adding Glyxambi comes up. You, being the
drug expert, are asked if this new medication
is worth putting on formulary. If so should
there be a prior authorization (PA)?