Transcript ACE inhibitor or ARB - 埼玉医科大学総合医療センター 内分泌・糖尿病

Journal Club
Suetonia C Palmer, Dimitris Mavridis, Eliano Navarese, Jonathan C Craig, Marcello Tonelli, Georgia
Salanti, Natasha Wiebe, Marinella Ruospo, David C Wheeler, Giovanni F M Strippoli
Comparative efficacy and safety of blood pressure-lowering agents
in adults with diabetes and kidney disease: a network meta-analysis
Lancet. Vol 385 May 23, 2015 .
James D. Lewis, MD, MSCE; Laurel A. Habel, PhD; Charles P. Quesenberry, PhD; Brian L. Strom, MD,
MPH; Tiffany Peng, MA; Monique M. Hedderson, PhD; Samantha F. Ehrlich, PhD; Ronac Mamtani, MD,
MSCE; Warren Bilker, PhD; David J. Vaughn, MD; Lisa Nessel, MSS, MLSP; Stephen K. Van Den Eeden,
PhD; Assiamira Ferrara, MD, PhD
Pioglitazone Use and Risk of Bladder Cancer and Other Common
Cancers in Persons With Diabetes
JAMA. 2015;314(3):265-277. doi:10.1001/jama.2015.7996
2015年8月06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
Sellami Mnif Houda
Article
Comparative effi cacy and safety of blood
pressure-lowering agents in adults with diabetes
and kidney disease: a network meta-analysis
Suetonia C Palmer, Dimitris Mavridis, Eliano Navarese, Jonathan C Craig,
Marcello Tonelli, Georgia Salanti, Natasha Wiebe, Marinella Ruospo, David C
Wheeler, Giovanni F M Strippoli
Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand (S C Palmer PhD); Department of
Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (D Mavridis PhD, G Salanti PhD);
Department of Primary Education, University of Ioannina, Ioannina, Greece (D Mavridis); Department of Cardiology and
Internal Medicine, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland (E Navarese PhD); Sydney
School of Public Health, University of Sydney, Sydney, Australia (Prof J C Craig PhD, Prof G F M Strippoli PhD); Cumming
School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada (Prof M Tonelli MD); Department of
Medicine, Division of Nephrology and Immunology, University of Alberta, AB, Canada (N Wiebe MMath); Department of
Translational Medicine, Division of Nephrology and Transplantation, Amedeo Avogadro University of Eastern Piedmont,
Novara, Italy (M Ruospo MSc); Diaverum Medical Scientifi c Offi ce, Diaverum Sweden AB, Lund, Sweden (M Ruospo, Prof G
F M Strippoli); Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy (Prof G F M Strippoli); and
Royal Free and University College Medical School, London, UK (Prof D C Wheeler MD) Correspondence to: Prof Giovanni F
M Strippoli, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
[email protected]
Lancet. Vol 385 May 23, 2015
-Diabetes
3–4% of adults worldwide
- CKD
25–40% of 20-25 Years diabetic
patients (the leading cause of end stage KD)
-BP lowering Agents has been central to the
treatment of diabetic kidney disease for decades
prevalence End Stage KD over the past 10 years
Objective
- To investigate the benefits and harms of blood
pressure lowering drugs in patients with
Diabetes and Kidney disease.
Methods
-Heterogeneity assessed with I² metric
-Random-effects network meta-analysis
-Random-effects pair-wise and network meta-analyses
to estimate primary and secondary outcomes
-Surface under the cumulative ranking (SUCRA)
probabilities used To rank the treatments for an outcome
The efficacy /safety percentage of every intervention
relative to an imaginary intervention that is always the
best without uncertainty .
RESULTS:
188 studies,45338 patients eligible (systematic review)
•157 studies included network analysis, 43 256 patients
• 7 drug classes alone / in combination were compared
with placebo or standard treatment
ACE inhibitors, ARBs, aldosterone antagonists, β
blockers, calcium-channel blockers, endothelin inhibitors,
and renin inhibitors.
• Mean age: 52·5 years (SD 12·0).
• 53 studies were exclusively of individuals with macro
albuminuria (9445 patients), and 102 studies were solely
of people with microalbuminuria (15 576 patients).
•9 studies were terminated early
• Risk of bias in studies was generally low
33 studies
No blood pressure-lowering strategy
was signifi cantly better than placebo
13 studies
11 studies
estimated treatment effects were
very imprecise and outcome
definitions were heterogeneous
14 studies
36 STUDIES
Most regimens were
efficacious
estimated effects of drug regimens on secondary cardiovascular
and safety outcomes
Myocardial infarction
(18 studies)
Stroke (15 studies)
and cardiovascular
ARB monotherapy was superior to placebo ( prevention
not significant / very imprecise
),other drugs were
non-significant
mortality (9 studies)
Hyperkalaemia (18
No drug regimen increased the risk of hyperkalaemia
studies)
ACE inh ARB comb : ranked low ( borderline higher risk than other
strategies)
Presyncope (33
studies)
Renin inhibitors raised the risk
Cough (38 studies)
Caused by Regimens containing: ACE inhibitor or ARB
Peripheral oedema (25
studies )
calcium-channel blocker monotherapy led to peripheral oedema
1-Estimated effects of drug regimens on blood pressure
Comparing to Placebo
•
•
Reductions in both systolic and
diastolic blood pressure for all
treatment regimens
Significant reductions in diastolic
blood pressure with :
Pairwise, network Meta-analyze
Diastolic blood pressure :
Dual ACE inhibitor and calcium-channel
blocker
Dias BP to a greater extent
than monotherapy ( calcium-channel
blocker, ACE inhibitor, ARB, or β
blocker).
-Renin inhibitors,
-ACE inhibitors / calcium-channel
blockers combination,
-Monotherapy with ald antagonists, Ca
channel blockers, and ACE
inhibitors
2- Results for all-cause mortality and end-stage kidney disease
Robust in sensitivity analyses
Important changes in treatment rankings were not evident
CONCLUSION
All cause mortality: No blood pressure-lowering strategy was superior to
placebo
ACE inh , ARB treatment (alone or in combination) , endothelin inhibitors : most
effective agents for prevention of end-stage kidney disease, only an ARB
(alone or combined with an ACE inhibitor) was significantly better than
placebo
Drug-induced acute kidney injury / hyperkalaemia : similar for all drugs,
although dual ACE inhibitor and ARB treatment : clinically important effect.
Drug effects on myocardial infarction, stroke, and cardiovascular mortality were
not significant for many blood pressure-lowering strategies.
Effects on blood pressure : not differ by treatment regimens, consistent with the
notion that pharmacological effects are independent of blood pressure lowering.
Dual ACE inhibitor and ARB TTT: effective for prevention of end-stage KD
challenges the 8th Joint National Committee (JNC 8) guidelines (against
combining these two treatments in this clinical setting) Inform the KDIGO
guidelines( 2012 concluded that although effects of dual blockade were
promising based on treatment reductions in proteinuria, the benefits of dual
treatment on clinically important renal outcomes remained unproven)
Concerns are justified about ACE inh and ARB combination ( diabetic kidney
disease)
the scary balance between potential benefits (survival and end-stage
kidney disease) and safety (acute kidney injury and hyper kalaemia).
ONTARGET (telmisartan and ramipril) increased the risk of a composite endpoint
of dialysis, doubling of serum creatinine, and death in high-risk patients with and
without diabetes, although notably the point estimate strongly favoured dual
treatment within a small subgroup of patients with overt diabetic nephropathy
VA NEPHRON-D study,(ARB monotherapy compared with ACE inhibitor and ARB
Comb treatment in adults with proteinuria and diabetes)
study was terminated early because of a high prevalence of acute kidney
injury and hyperkalaemia in patients receiving dual treatment
In absolute terms, study’s findings suggest that:
ACE inhibitor and an ARB Comb to 1000 adults ( diabetes and kidney
disease) a for 1 year
- Might Prevent 14 patients
developing end-stage kidney disease
-Induce regression of albuminuria in
208 people
- At the cost of 55 patients having
acute kidney injury
-135 individuals developing
hyperkalaemia.
Treatment with an ARB alone in 1000 patients over 1 year
-Might prevent 11 cases of end-stage
kidney disease
-Induce regression of albuminuria in
118 people,
Lead to acute kidney injury in 17
patients and hyperkalaemia in 70
individuals.
Current international guidelines for management of blood pressure in chronic
kidney disease suggest that ACE inhibitors and ARBs are similarly effective at
protecting against kidney failure ( same as The findings of this network metaanalysis and for mortality and adverse treatment effects )
Concerning ACE inhibitor and calcium-channel blocker : The high SUCRA
ranking of dual treatment for several endpoints, including mortality, surrogate renal
outcomes, acute kidney injury, and blood pressure control, suggests that future
trials of this drug combination are needed and would strongly inform clinical practice
Renin inhibitors and endothelin antagonists:
Renin inhibitors augmented kidney failure and treatment estimates accorded with
worsening end-stage KD, without evidence for improved survival or diminished
cardiovascular events.
Endothelin inhibitors : possibly beneficial in terms of kidney function, and should be
used with caution until additional data are available with respect to cardiovascular
outcomes.
LIMITATION:
First, because of scant primary data, effects of blood pressure treatment on
cardiovascular events and related mortality were very uncertain
Second, data for the outcome of end-stage kidney disease were restricted
largely to patients who had macroalbuminuria and those with type 2 diabetes.
Third, acute kidney injury was defined poorly, and scant evidence relating to this
outcome does not allow us to make proper estimates of the risk–benefit ratio of
blood pressure-lowering treatments in diabetic kidney disease.
Fourth, few data were available from countries of low-to-middle income.
Fifth, we did not control for dose in our analyses.
1Center
for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia
of Biostatistics and Epidemiology, University of Pennsylvania
3Department of Medicine, University of Pennsylvania
4Division of Research, Kaiser Permanente Northern California, Oakland
5Rutgers Biomedical and Health Sciences, New Brunswick, New Jersey
2Department
JAMA. 2015;314(3):265-277. doi:10.1001/jama.2015.7996
Article
Pioglitazone Use and Risk of Bladder Cancer and
Other Common Cancers in Persons With
Diabetes
James D. Lewis, MD, MSCE; Laurel A. Habel, PhD; Charles P. Quesenberry,
PhD; Brian L. Strom, MD, MPH; Tiffany Peng, MA; Monique M. Hedderson,
PhD; Samantha F. Ehrlich, PhD; Ronac Mamtani, MD, MSCE; Warren Bilker,
PhD; David J. Vaughn, MD; Lisa Nessel, MSS, MLSP
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia (Lewis, Strom,
Mamtani, Bilker, Nessel); Department of Biostatistics and Epidemiology, University of Pennsylvania (Lewis,
Strom, Mamtani, Bilker); Department of Medicine, University of Pennsylvania (Lewis, Mamtani, Vaughn);
Division of Research, Kaiser Permanente Northern California, Oakland (Habel, Quesenberry, Peng,
Hedderson, Ehrlich, Van Den Eeden, Ferrara); Rutgers Biomedical and Health Sciences, New Brunswick,
New Jersey (Strom)
JAMA. 2015;314(3):265-277. doi:10.1001/jama.2015.7996
TZD have been used to treat up to 26% of persons with diabetes
mellitus
Pioglitazone is the only TZD commonly used worldwide today
A higher incidence of bladder cancer was observed in premarketing
studies of pioglitazone in male rats
1- In 2003, the US Food and Drug Administration and the
manufacturer agreed to this 10-year observational study to evaluate
the potential risk of bladder cancer with pioglitazone use in humans.
Shortly thereafter, the European Medicines Agency requested a
second postmarketing investigation of pioglitazone use and risk of
cancer at other sites
2- (Diabetes Care 2011) Interim analyses of 10 other cancers : no
statistically significant association but the maximum duration of
follow-up was fewer than 6 years
the European
Medicines Agency requested that follow-up be extended.
Here the results for the extended follow-up for
both investigations
OBJECTIVE:
-To examine whether pioglitazone use for diabetes
is associated with risk of bladder and 10 additional
cancers
METHODS:
Cohort and nested case-control study conducted within Kaiser Permanente Northern
California (KPNC) among persons with diabetes , using electronic health records .
Eligibility:
Persons who met any of the following criteria
1. Received a diagnosis of diabetes as of January 1, 1997, aged 40 years or older, and
were members of KPNC;
2. Had received a diagnosis of diabetes, were aged 40 years between January 1, 1997,
and December 31, 2002, for the bladder cancer analyses or December 31, 2005, for
the 10 cancer analyses and were KPNC members on their 40th birthday
3. Had diabetes and were aged 40 years or older when they joined KPNC between
January 1, 1997, and December 31, 2002, for the bladder cancer analyses or June
30, 2005, for the 10 cancer analyses.
EXCLUSION:
Persons without prescription benefits on entry into the cohort / with a greater than 4
month gap in prescription / membership benefits starting within 4 months of entering
the cohort/ Persons receiving a diagnosis of bladder cancer before cohort entry or
within 6 months of joining KPNC and persons with a diagnosis of any cancer before
cohort entry were excluded from the Bladder/10- cancer cohort
Follow-up:
Started when the inclusion criteria were first met and ended with the first of the
following:
Gap of greater than 4 months in membership or prescription benefits, incident
bladder cancer for the bladder cancer analyses or any cancer for the 10 cancer
analyses, death, or December 31, 2012, for the bladder cancer analyses or June 30,
2012, for the 10-cancer analyses
Use of pioglitazone and other diabetes medications :
Defined as having filled 2 prescriptions for the drug within a 6-month period. Once a
patientmet the exposure definition, he or she was considered exposed from that
point forward
The final cohort included 193 099 persons with diabetes, of
whom 34 181 received pioglitazone during follow-up
RESULTS
Pioglitazone Use and the Risk of
Bladder Cancer
The crude incidence of bladder cancer was 89.8 and 75.9 per 100 000 personyears in pioglitazone users and nonusers, respectively.
Cancer stage did not differ between pioglitazone users and nonusers
Same for metformin, sulfonylureas, insulin,
and other thiazolidinediones users
Additional analyses were conducted to explore differences between the 5-year
interim results and the results with extended follow-up
Analyses using the dose and duration categories from the interim report
and finer gradation of long-term use produced results similar to those of the
extended follow-up analyses
Pioglitazone Use and the Risk of Cancer
at 10 Sites Other Than the Bladder
Ever use of insulin was associated with a decreased risk of prostate
cancer (HR, 0.90; 95% CI, 0.81-0.99).
Ever use of metformin (HR, 1.21; 95% CI, 1.02-1.43), insulin (HR, 2.34;
95% CI, 1.97-2.78), and sulfonylureas (HR, 1.49; 95% CI, 1.22-1.81) and
never having 2 prescriptions of a diabetes medication from the same
class within 6 months (HR, 1.55; 95% CI, 1.02-2.36) were each
associated with increased risk of pancreatic cancer
Users of pioglitazone more commonly had local-stage prostate cancer
and less commonly had local-stage pancreatic cancer
Pioglitazone users less commonly had well or moderately differentiated
prostate cancers (0.4% and 53.2%) compared with never users (1.6%
and 58.2%; P = .002 after excluding the undetermined).
Several sensitivity analyses were conducted , Estimates were largely
unchanged, although the weak linear trends for increasing breast cancer
risk with increasing pioglitazone cumulative dose and duration of use
became statistically significant
Conclusion:
There was no statistically significant increased risk of bladder
cancer associated with pioglitazone use. However, a small
increased risk, as previously observed, could not be excluded.
The increased prostate and pancreatic cancer risks
associated with ever use of pioglitazone merit further
investigation to assess whether the observed associations are
causal or due to chance, residual confounding, or reverse
causality
Message
ピオグリタゾン、膵癌と前立腺癌リスク増
ピオグリタゾン使用と膀胱癌および他の10種の癌
リスクとの関連を、40歳以上の糖尿病患者約20万
人のコホート分析およびコホート内症例対照分析
で検 証。ピオグリタゾン使用は、膀胱癌の統計的
有意なリスク増加と関連せず（調整後ハザード比
1.06）、前立腺癌および膵臓癌のリスク増加と関
連した（同 1.13、1.41）。
http://www.m3.com/clinical/journal/15675