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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