Clinical Trial Discussion Activity

11/09/16

Prepared by: Sandra R. Bai, PharmD

Lecture outline
1. Review of background information
2. Information in the lay press
3. Small group discussion questions
4. Class review of discussion questions
5. Opinions from experts
6. Advisory Committees- Nicolette Mehas

Diabetes and cardiovascular risk

Heart disease noted on 68% of diabetes-related death certificates for
patients 65 yoa+ in 2004
Stroke noted on 16% of diabetes-related death certificates for
patients 65 yoa+ in 2004
The risk of death from cardiovascular causes for adults with diabetes
is 2-4x higher than adults without diabetes
The risk of stroke for adults with diabetes is 2-4x higher than adults
without diabetes

CDC. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of
Health and Human Services, Centers for Disease Control and Preventions, 2011.

 FDA Guidance documents for industry that applies to all diabetes drugs currently
under development released in 2008
Key Changes:
1. Upper bound of the 95% for the risk ratio of important CV events of <1.3 should be used as
a key criterion for excluding unacceptable CV risk for new treatments of type 2 diabetes
2. Study patients must include those with relatively advanced disease, elderly patients, and
patients with some degree of renal impairment
3. A minimum of 2 years CV safety data must be provided
4. All phase 2 and 3 studies should include a prospective, independent adjudication of CV
events. Adjucated events should include CV mortality, MI, stroke, and can include
hospitalization for ACS, urgent revascularization procedures, and possibly other endpoints
5.For satisfaction of the new statistical guidelines, the analysis of CV events may include a
meta-analysis of all placebo-controlled trials, add on trials, and active-controlled trials or an
additional single large safety trial may be conducted that alone, or added to other trials,
would be able to satisfy this upper bound
FDA. Guidance for Industry, Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, 2008. Silver Spring, MD: U.S.
Department of Health and Human Services, Food and Drug Administration, 2008.

Rise and fall of rosiglitazone

The Rise
May 1999: FDA approves rosiglitazone despite reviewer concerns about adverse lipid
effects, edema, and myocardial ischemia
July 1999: A prominent endocrinologist publicly raises concerns about the CV safety of
rosiglitazone. He is forced to sign an agreement promising not to express his concerns
December 2006: Peak sales of $3.3 billon annually

The Fall
May 2007: Meta-analysis of CV outcomes with rosiglitazone published online in NEJM
reporting an increases heart attack risk
July 2007: FDA finds a statistically significant increase in risk (RR=1.4)
June 2009: An adequately powered CV outcomes study is started
November 2011: Prescribing and dispensing restrictions removed
December 2015: REMS eliminated
Nissin SE. The rise and fall of rosiglitazone. Eur Heart J 2010 Apr;31(7):773-6.

Empagliflozin
Rationale for cardiovascular benefit:
Weight loss
Reductions in blood pressure
Favorable effects on markers of arterial stiffness, vascular resistance, visceral
adiposity, albuminuria, and plasma urate

Metformin
Shown to reduce cardiovascular complications:
Favorable effects on lipid profile
Improves endothelial function unrelated to glycemic control
Weight neutral
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015 Nov 26;373(22):2117-28.
Triggle CR, Ding H. Cardiovascular impact of drugs used in the treatment of diabetes. Ther Adv Chronic Dis 2014 Nov;5(6):245-268.

EMPA-REG in the news

Pollack A. Jardiance, a Diabetes Drug, Cut Cardiovascular Deaths by 38%, Study Says. New York Times.

In Class Clinical Trial Discussion Activity

11/09/16

Question #1
Was the study design appropriate to meet the
study objectives?

Question #2
Were the study interventions appropriate?

Question #3
Were the inclusion and exclusion criteria
appropriate?

Question #4
Was the primary outcome appropriate?

Question #5
Was the secondary outcome appropriate?

Question #6
Explain the conclusions that can be drawn
from the data presented in Figure S1

Question #7
What does table S2 tell you about the study
population?

Question #8
Explain the conclusions that can be drawn
from the data presented in Table 1

iClicker
Calculate the NNT for the primary composite outcome
A.
B.
C.
D.

60
63
58
65

iClicker
Calculate the NNH for genital infections (pooled empagliflozin group)
A.55
B. 63
C. 18
D. 22

Question #9
What were the overall strengths of this study?

Strengths
Randomized, double blind, controlled study decreases confounding variables
Stratification based on geographical region, renal function, baseline A1c, BMI
improves internal validity by confounding.
Multicenter, multinational design increases external validity
Length of trial sufficient to provide long-term safety information
Independent academic data monitoring committee reviewed safety data every 90
days reduces bias
Independent adjudication of cardiovascular outcome events and deaths
improves internal validity
Investigators were encouraged to treat cardiovascular risk factors to achieve the
best available standard of care which improves internal validity

Question #10
What were the overall limitations of this
study?

Limitations
Composite endpoint could be misleading as there was no difference in the individual components (fatal or
nonfatal MI, hospitalization for unstable angina, coronary revascularization procedure, fatal or nonfatal
stroke, TIA). Death from any cause and death from cardiovascular causes were main drivers of the
composite.
Not all patients were on standard of care at baseline (however it was balanced between tx groups)
The majority of subjects were Caucasian could limit external validity
The majority of subjects were male could limit external validity
Primary endpoint, while statistically significant, may not be clinically significant given the small absolute
difference (1.6%) over 2.6 years of therapy.
Individual dose effects were not significant. Statistical significance was only demonstrated with pooled data
Despite appropriate doses of empagliflozin, an absolute difference of only 0.35% in A1C levels
demonstrated
Numerous protocol changes throughout study duration limits reproducibility of a second study
Investigators were encouraged to treat other CV factors using the standard of care and guidelines for that
center which could reduce internal validity because guidelines/standard of care could differ per center

iClicker
Would you recommend the addition of empagliflozin in
patients with diabetes at a high CV risk?

A. Yes
B. No

What are experts saying about

the EMPA-REG trial?