e206 Diabetes Care Volume 37, September 2014

RESPONSE TO COMMENTS ON ZHANG ET AL. Yuanhui Zhang,1 Rozalina G. McCoy,2

Jennifer E. Mason,3 Steven A. Smith,2,4
Second-Line Agents for Glycemic Control Nilay D. Shah,4,5 and Brian T. Denton6

for Type 2 Diabetes: Are Newer Agents

Better? Diabetes Care 2014;37:13381345
Diabetes Care 2014;37:e206e207 | DOI: 10.2337/dc14-1339

We are grateful for the comments from
Messori and Bellia (1) and those of Bae
et al. (2) regarding our article (3). We
hope the following response will clarify
the questions they raised.
Messori and Bellia (1) pointed out
that the incremental cost-effectiveness
ratio (ICER) is preferred over the abso-
lute cost-effectiveness ratio. We agree,
and it is worth noting that Fig. 1 in our
article provides complete details about
the expected quality-adjusted life-years
(QALYs) prior to rst events and the ex-
pected medication costs under all treat-
ment regiments. As such, it subsumes
ICER estimates. Admittedly, the readers
must calculate them from the graph and
therefore we provide the estimates for
the glycemic control goal of HbA1c ,7%
here. For males, for regimens T1-T4 the
ICERs in units of $/QALY are 10,369,
e-LETTERS COMMENTS AND RESPONSES
Bae et al. question an apparent as-
sumption in our model that underlying
HbA1c uctuation at baseline remains
constant throughout the patients life
(2). However, we did not assume a con-
stant baseline; we assumed a linear
increasing trend in HbA1c, consistent
with other published glycemic control
models (4,5).
Bae et al. suggested the use of treat-
ment effect estimates, based on real-
world data, is a major limitation. We
take the contrary perspective, i.e., that
this is a strength of our study, as real-
world data accounts for potential lack of
adherence and other behavioral factors
that may not be present in the ideal set-
ting of a randomized controlled trial
(RCT). Of course, we also recognize the
merit of RCTs in limiting bias, and for this
reason we reported results based on
similar or decreased treatment effects
for the newer medications. Bae et al.
also suggested the use of propensity
score methods to account for possible
confounding. This would be interesting
to explore in theory, but in practice
there are likely a number of unmea-
sured confounders. Fortunately, our
sensitivity analysis based on RCT esti-
mates obviates all of these concerns.
Bae et al. fairly criticize the fact that
the cost of hypoglycemia was not in-
cluded in the model. As they pointed
out, we adjusted for hypoglycemia out-
comes, but not for cost. The source they
cite provides an estimate of the cost of
hypoglycemia hospitalization of $17,564
per event for an inpatient admission,
$1,387 for an emergency department
visit, and $394 for an outpatient visit.
The source also provides overall inci-

11,062, 11,277, 11,144, respectively. For
females, for regimens T1-T4 the ICERs are
9,310, 9,865, 10,043, 9,933, respectively.
Messori and Bellia also express confu-
sion over the computation of life-years
to rst event. To clarify, our reported
results are based on a median diagnosis
age between 54 and 55 years. The life-
years to rst event are the sum of time to
diagnosis and the time from diagnosis to
rst event, where the latter is computed
using our model.
treatment effects reported in RCTs. As
readers can see from our results, these
do not change our main conclusions.
Bae et al. propose the use of a longer
time window for measuring the effect of
medications. In our analysis, we found
no evidence that a longer time window
would make a signicant difference.
Compared with the 3-month time win-
dow used in our article, the use of 6- and
12-month time windows before and
after treatment initiation resulted in
dence rates for each event type. The
estimated time frame for the newer
medications, from Table 2 of our article,
was 1.59 to 2.76 years. Using the upper
bound of 2.76 years as an estimate of
the time on medication, the total aver-
age cost per patient due to hypoglyce-
mia is conservatively estimated at $89.
Assuming all events are attributed to
sulfonylurea and none to the newer
medications, this estimate would not
change any of our conclusions.

1
Graduate Program in Operations Research, North Carolina State University, Raleigh, NC
2
Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
3
Department of Public Health Sciences, University of Virginia, Charlottesville, VA
4
Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, MN
5
Optum Labs, Cambridge, MA
6
Department of Industrial and Operations Engineering, University of Michigan, Ann Arbor, MI
Corresponding author: Brian T. Denton, btdenton@umich.edu.
2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for prot,
and the work is not altered.
care.diabetesjournals.org
Bae et al. also cite a recent source sug-
gesting an average cost of $127 per person
per event for nonsevere hypoglycemic
events (6). However, Brod et al. (6) studied
both type 1 and type 2 diabetes. In their
study, 74% of patients reported using
insulin and patients on oral medications
reported a lower impact on work pro-
ductivity and less work absenteeism,
which were the primary factors attrib-
uted to the cost of nonsevere hypogly-
cemia events.
In summary, none of the concerns
raised change the conclusions reported
in our article. We appreciate the oppor-
tunity to elaborate on these aspects
of our study to provide a better under-
standing of our results and conclusions.
better? Diabetes Care 2014;37:13381345
Duality of Interest. No potential conicts of
interest relevant to this article were reported.
References
1. Messori A, Bellia A. Comment on Zhang et al.
Second-line agents for glycemic control for type
2 diabetes: are newer agents better? Diabetes
Care 2014;37:13381345 (Letter). Diabetes
Care 2014;37:e205. DOI: 10.2337/dc14-0983
2. Bae J, Curtis BH, Kendall DM, Heine RJ. Comment
on Zhang et al. Second-line agents for glycemic con-
trol for type 2 diabetes: are newer agents better?
Diabetes Care 2014;37:13381345 (Letter). Diabe-
tes Care 2014;37:e204. DOI: 10.2337/dc14-1041
Zhang and Associates e207
3. Zhang Y, McCoy RG, Mason JE, Smith SA, Shah
ND, Denton BT. Second-line agents for glycemic
control for type 2 diabetes: are newer agents
4. CDC Diabetes Cost-effectiveness Group.
Cost-effectiveness of intensive glycemic con-
trol, intensied hypertension control, and se-
rum cholesterol level reduction for type 2
diabetes. JAMA 2002;287:25422551
5. Chen J, Alemao E, Yin D, Cook J. Development
of a diabetes treatment simulation model: with
application to assessing alternative treatment in-
tensication strategies on survival and diabetes-
related complications. Diabetes Obes Metab
2008;10(Suppl. 1):3342
6. Brod M, Wolden M, Christensen T, Bushnell DM.
Understanding the economic burden of nonsevere
nocturnal hypoglycemic events: impact on work
productivity, disease management, and resource
utilization. Value Health 2013;16:11401149