Journal Club
Dziuba J, Alperin P, Racketa J, Iloeje U, Goswami D, Hardy E,
Perlstein I, Grossman HL, Cohen M.
Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus
standard diabetes therapy on cardiovascular and microvascular
outcomes.
Diabetes Obes Metab. 2014 Jul;16(7):628-35.
2014年8月28日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
Diabetologia 55:1577-96, 2012, Diabetes Care 35:1364-1379, 2012
Aims
Dapagliflozin, a sodium-glucose cotransporter 2
(SGLT-2) inhibitor, has been shown to lower
glycated hemoglobin (HbA1c), weight, blood
pressure and serum uric acid in clinical trials.
Plasma lipids were also evaluated as exploratory
variables. The goal of this study was to estimate
the long-term cardiovascular (CV) and
microvascular outcomes of dapagliflozin added to
the standard of care (SOC) versus SOC using
simulation methodology.
Methods
The Archimedes Model, a validated model of human
physiology, diseases and healthcare systems, was used to
model a type 2 diabetes mellitus (T2DM) population derived
from National Health and Nutrition Examination Survey
(NHANES) with HbA1c 7–10%, taking a single oral antidiabetic
agent [metformin, sulfonylureas SU or thiazolidinedione (TZD)]
at the beginning of the trial. A 20-year trial was simulated
comparing dapagliflozin 10 mg, given in addition to SOC, with
SOC alone. SOC was based on American Diabetes Association
(ADA)/European Association for the Study of Diabetes (EASD)
2012 guidelines and included diet, metformin, SU, TZD,
dipeptidyl peptidase-4 (DPP-4), glucagon-like peptide-1 (GLP1), and insulin therapies, with usage levels reflective of those in
NHANES. Dapagliflozin effects were derived from phase 3
clinical trial results. End points included CV and microvascular
outcomes.
We evaluated dapagliflozin as an add-on therapy in patients with T2DM uncontrolled on
established DM oral monotherapy treatment [i.e. metformin, sulfonylureas (SU), or
thiazolidinedione (TZD)]. We created a simulated population of 30 000 per treatment strategy
by using person-specific data from the NHANES (years 1999–2008).
A possible consequence of this could be an overestimation of benefit from SGLT2 inhibitors
due to a lower than expected usage of statins and/or glucagon-like peptide-1 (GLP1)/dipeptidyl peptidase-4 (DPP-4) therapies.
The first, dapagliflozin-1, included the glucose-, BP-, weight- and SUA-lowering effects
associated with dapagliflozin. The second, dapagliflozin-2, included these effects plus
effects on lipids. Because we aimed to evaluate dapagliflozin as an add-on therapy to
established T2DM monotherapy treatments, our efficacy assumptions (Table 1) were based
on pooled data from phase III clinical trials that evaluated dapagliflozin as an add-on
treatment to metformin, SU and TZD, including four studies that assessed HbA1c, weight,
SUA and the lipid panel [7-10]. Assumptions for BP change were based on results from two
add-ons to usual care studies that assessed systolic BP(SBP) as a key secondary end point
[11, 12].
In all treatment strategies the trial protocol began with
an initial visit at the start of the simulated trial. Patients
included in the study were uncontrolled on T2DM
monotherapy treatment. In the SOC arm, patients were
prescribed second-line SOC diabetes treatments. In the
dapagliflozin arms, the patients were prescribed
dapagliflozin. In all arms, a follow-up visit was
scheduled in 3 months. At this visit and with subsequent
follow-up care additional treatments were prescribed to
patients with HbA1c > 7.0% (uncontrolled) according to
the 2012 ADA/EASD guidelines. Follow-up visits were
scheduled every 3 months if uncontrolled and every
6 months if controlled.
5.3mM=205mg/dl
T-chol
5mM=193mg/dl
1.3mM=50mg/dl
1.1mM=42mg/dl
2.65mM=235mg/dl
TG
2.25mM=199mg/dl
HDL-C
3mM=116mg/dl
2.75mM=106mg/dl
LDL-C
SOC
Dapagliflozin-1
Dapagliflozin-2
Figure 4. Number needed to treat with dapagliflozin-1 and dapagliflozin-2 treatments to avoid an
outcome relative to standard of care (SOC) at 20 years among uncontrolled type 2 diabetes mellitus
(T2DM) cohort. [MACE, major adverse cardiovascular events (fatal and non-fatal MI, fatal and nonfatal stroke along with CV death), expanded MACE, MACE and foot amputation; MI, myocardial
infarction; CV, cardiovascular; ESRD, end-stage renal disease].
Results
Over a 20-year period, patients on dapagliflozin
were projected to experience relative reductions
in the incidence of myocardial infarction (MI),
stroke, CV death, and all-cause death of 13.8,
9.1, 9.6 and 5.0%, respectively, and relative
reductions in the incidence of end-stage renal
disease (ESRD), foot amputation, and diabetic
retinopathy of 18.7, 13.0 and 9.8%, respectively,
when compared with SOC.
Conclusions
On the basis of simulation results, adding
dapagliflozin to currently available treatment
options is projected to further decrease the
CV and microvascular complications
associated with T2DM.
Message
SGLT2阻害薬をこれまでの標準的な治療に追加で
用いると血管合併症の低下が予想されるという
結果である。
副作用やドロップアウトについては？
実際の薬の使い方のウェイトにより結果は変わ
ると思われるので、この解析はどのくらい現実
をシミュレートできているのか疑問。特に日本
ではDPP-4阻害薬をもっと使うのでかなり現実と
異なっていると感じる。