Journal Club
Jackevicius CA, Tu JV, Ross JS, Ko DT, Carreon D, Krumholz HM.
Use of fibrates in the United States and Canada.
JAMA. 2011 Mar 23;305(12):1217-24.
Hovorka R, Kumareswaran K, Harris J, Allen JM, Elleri D, Xing D, Kollman
C, Nodale M, Murphy HR, Dunger DB, Amiel SA, Heller SR, Wilinska ME,
Evans ML.
Overnight closed loop insulin delivery (artificial pancreas) in adults with type
1 diabetes: crossover randomised controlled studies.
BMJ. 2011 Apr 13;342:d1855. doi: 10.1136/bmj.d1855.
2011年4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
N Engl J Med. 2010 Apr 29;362(17):1563-74. Epub 2010 Mar 14.
primary-prevention trial with
gemfibrozil in middle-aged men
with dyslipidemia. Safety of
treatment, changes in risk
factors, and incidence of
coronary heart disease. N Engl J
Med 1987;317:1237-45.
Secondary prevention by raising
HDL cholesterol and reducing
triglycerides in patients with
coronary artery disease: the
Bezafibrate Infarction Prevention
(BIP) study. Circulation
2000;102:21-7.
Effects of long-term fenofibrate
therapy on cardiovascular events
in 9795 people with type 2
diabetes mellitus Lancet
2005;366:1849-61.
Department of Pharmacy Practice and Administration, College of
Pharmacy, Western University of Health Sciences, Pomona, California
(Drs Jackevicius and Carreon); Institute for Clinical Evaluative
Sciences, Toronto, Ontario, Canada (Drs Jackevicius, Tu, and Ko);
Department of Health Policy, Management, and Evaluation, Faculty of
Medicine (Drs Jackevicius and Tu) and Division of Cardiology,
Schulich Heart Centre, Sunnybrook Health Sciences Centre (Drs Tu
and Ko), University of Toronto, Toronto, Ontario, Canada; Veterans
Affairs Greater Los Angeles Healthcare System, Los Angeles,
California (Dr Jackevicius); University Health Network, Toronto,
Ontario, Canada (Dr Jackevicius); Department of Medicine, Section of
General Internal Medicine (Dr Ross), Department of Epidemiology and
Public Health, Section of Health Policy and Administration (Dr
Krumholz), and Section of Cardiovascular Medicine (Dr Krumholz),
Yale University School of Medicine, Center for Outcomes Research
and Evaluation, Yale NewHaven Hospital,NewHaven, Connecticut
(Drs Ross and Krumholz); and RobertWoodJohnson Clinical Scholars
Program, New Haven, Connecticut (Dr Krumholz)
JAMA. 2011;305(12):1217-1224
Context
Interest in the role of fibrates intensified after the
publication of the negative results from the
Action to Control Cardiovascular Risk in
Diabetes (ACCORD) trial, which assessed
therapy with fenofibrate plus statins. The
evidence for clinical benefit in outcomes with the
use of fibrates is heavily weighted on the use of
the older fibrates such as gemfibrozil and
clofibrate.
Objectives
To examine trends in the current use of fibrates and to
examine the relationship between differences in the
availability and use of brand-name vs generic
formulations of fenofibrate and the economic
implications in the United States compared with Canada.
Design, Setting, and Patients
Population-level, observational cohort study using IMS
Health data from the United States and Canada of
patients prescribed fibrates between January 2002 and
December 2009.
Main Outcome Measures
Fibrate prescriptions dispensed and expenditures.
Figure 1. Fibrate Prescriptions in the United States and Canada per 100 000 Population per Month
Data are from the National Prescription Audit of IMS Health United States and the CompuScript Audit of IMS Health Canada.
Figure 1. Fibrate Prescriptions in the United States and Canada per 100 000 Population per Month
Data are from the National Prescription Audit of IMS Health United States and the CompuScript Audit of IMS Health Canada.
Figure 3. Brand and Generic
Fibrate Prescriptions in the
United States and Canada per
100 000 Population per Month
Data are from the National
Prescription Audit of IMS Health
United States and the CompuScript
Audit of IMS Health Canada. The
predominant generic version of Lipidil
Supra received approval for market in
April 2006.
COMMENT
This pattern is paradoxical to declines that might have been expected because the
only clinical outcomes evidence for fenofibrate during our study period was the FIELD
trial, which failed to find a significant reduction in the primary end point of coronary
events in a diabetic population.
The US pattern is unusual in that brand-name formulations typically comprise
approximately25% to 30%of the product market share for medications 12 years
postmarket launch.
The preferential use of brand-name fibrate products continues with the latest product
Trilipix (which is the active metabolite of fenofibrate), showing a rate of increase in
use that far exceeds even that for fenofibrate, even though this specific formulation
has yet to be evaluated in clinical outcomes studies. Trilipix is approved for use with
statins, while all other fibrates have warnings against combined use with statins.
Current US guidelines recommend that fibrates without regard to type should only be
considered for reducing very high levels of triglycerides to prevent pancreatitis, for
treatment of dysbetalipoproteinemia, and as supplemental therapy to statins in
patients with diabetes and high non–high-density lipoprotein cholesterol. The 2006
revision of the Canadian guidelines now more cautiously reserves treatment with
fibrates for severe hypertriglyceridemia.
Results
In the United States, fibrate prescriptions dispensed increased from 336
prescriptions/ 100 000 population in January 2002 to 730 prescriptions/100 000
population in December 2009, an increase of 117.1% (95% confidence interval
[CI], 116.0%- 117.9%), whereas in Canada, fibrate prescriptions increased from
402 prescriptions/ 100 000 population in January 2002 to 474 prescriptions/100
000 population in December 2009, an increase of 18.1% (95% CI, 17.9%18.3%) (P＜.001). In the United States, fenofibrate prescriptions dispensed
increased from 150 prescriptions/100 000 population in January 2002 to 440
prescriptions/100 000 population in December 2009, an increase of 159.3%
(95% CI, 157.7%-161.0%), comprising 47.9% of total fibrate prescriptions in
2002 and 65.2% in 2009. In Canada, fenofibrate prescriptions increased from
321 prescriptions/100 000 population in January 2002 to 429 prescriptions/ 100
000 population in December 2009. The annual ratio of generic to brandname
fenofibrate use in the United States ranged from 0:1 to 0.09:1 between 2002
and 2008, while the ratio in Canada steadily increased from 0.51:1 to 1.89:1
between 2005 and 2008. In the United States, crude fenofibrate expenditures
increased from $11 535/100 000 population/month in 2002 to $44 975/100 000
population/month in 2009, while the rates in Canada declined from $17 695/100
000 population/ month in 2002 to $16 112/100 000 population/month in 2009.
Fibrate expenditures per 100 000 population were 3-fold higher in 2009 in the
United States compared with Canada.
Conclusion
During the past decade, prescriptions for
fibrates (particularly fenofibrate) increased
in the United States, while prescriptions for
fibrates in Canada remained stable.
Message/Comments
2002-09年の米国とカナダにおけるフィブラート
系薬剤の処方動向や後発医薬品の使用状況等を
観察コホート研究で検証。フィブラート系薬剤
処方の増加率は米国で117.1％、カナダで18.1％
であったが、フェノフィブラートの後発医薬品
の使用比率はカナダで高かった。2009年におけ
る米国のフィブラート系薬剤の消費額はカナダ
の3倍だった。
めちゃくちゃTGが高い人が米国では増えている
のではないか？
Figure A4: Plasma glucose, insulin
infusion, and plasma insulin during
APCam03 (n = 9)
Distribution of insulin infusion rates during APCam03
Manual closed-loop insulin delivery in
children and adolescents with type 1 diabetes:
a phase 2 randomised crossover trial.
Lancet 2010; 375: 743–51
BMJ 2011;342:d1855
Objective
To compare the safety and efficacy of
overnight closed loop delivery of insulin
(artificial pancreas) with conventional
insulin pump therapy in adults with type 1
diabetes.
The study was performed on type 1 diabetic pediatric patients using pumps and
meters from Smiths Medical, Medtronic, and Abbott.
Design Two sequential, open label, randomised controlled crossover, single
centre studies.
Setting Clinical research facility. Participants 24 adults (10 men, 14 women)
with type 1 diabetes, aged 18-65, who had used insulin pump therapy for at
least three months: 12 were tested after consuming a medium sized meal and
the other 12 after consuming a larger meal accompanied by alcohol.
Intervention During overnight closed loop delivery, sensor measurements of
glucose were fed into a computer algorithm, which advised on insulin pump
infusion rates at 15 minute intervals. During control nights, conventional insulin
pump settings were applied. One study compared closed loop delivery of insulin
with conventional pump therapy after a medium sized evening meal (60 g of
carbohydrates) at 1900, depicting the scenario of “eating in.” The other study
was carried out after a later large evening meal (100 g of carbohydrates) at
2030, accompanied by white wine (0.75 g/kg ethanol) and depicted the
scenario of “eating out.”
Main outcome measures The primary outcome was the time plasma glucose
levels were in target (3.91-8.0 mmol/L) during closed loop delivery and a
comparable control period. Secondary outcomes included pooled data analysis
and time plasma glucose levels were below target (≤3.9 mmol/L).
Closed loop algorithm
We used an algorithm based on the model predictive control approach. Every 15
minutes a research nurse initiated a control cycle; the nurse inputted the sensor glucose
value into the computer based algorithm and adjusted the insulin pump according to the
basal infusion rate calculated by the algorithm. The calculations utilised a compartment
model of glucose kinetics, describing the effect of rapid acting insulin and the
carbohydrate content of meals on glucose excursions detected by the sensor. The
algorithm was initialised using participant’s weight, total daily insulin dose, and basal
insulin requirements. Additionally, the algorithm was provided with glucose levels
measured by the sensor during a 30 minute period preceding the start of closed loop
delivery, the carbohydrate content of the evening meal, and the prandial insulin bolus.
The algorithm adapted itself to participants by updating two model variables: an
endogenous glucose flux correcting for errors in model based predictions, and
carbohydrate bioavailability. Several competing models differing in the absorption of
subcutaneous insulin and oral carbohydrates ran in parallel. A combined model
forecasted plasma glucose excursions over a 2.5 hour prediction horizon. The algorithm
aimed to achieve glucose levels between 5.8 (104) and 7.3 (131) mmol/L (mg/dl) and
adjusted the actual level depending on fasting versus postprandial status, preceding
glucose levels, and the accuracy of predictions made by the compartment model. Safety
rules limited maximum insulin infusion and suspended insulin delivery when the sensor
measured glucose at or below 4.3 mmol/L or when the sensor detected that glucose was
decreasing rapidly. We used algorithm version 0.02.04 to 0.02.18.
Fig 3
Profiles (medians and
interquartile ranges) of plasma
glucose and insulin
concentrations and insulin
infusion in eating in scenario
(12 participants). Outlying
squares represent
hypoglycaemic events
(glucose level <3.0 mmol/L)
Fig 4
Profiles (medians and
interquartile ranges) of plasma
glucose and insulin
concentrations and insulin
infusion in the eating out
scenario (12 participants).
Outlying squares represent
hypoglycaemic events
(glucose level <3.0 mmol/L)
Cumulative probabilities of plasma glucose
(solid lines) and sensor glucose (dashed
lines) during closed-loop insulin delivery
from midnight to the end of closed-loop (red
lines) and during continuous subcutaneous
insulin infusion (grey lines) combining data
observed in 2 scenarios.
Cumulative probability of plasma glucose
(solid lines) and sensor glucose (dashed
lines) during closed-loop insulin delivery
from start of closed-loop to the end of
closed-loop (red lines) and during
continuous subcutaneous insulin infusion
(grey lines) combining data observed in
eating in scenarios.
Results
For the eating in scenario, overnight closed loop delivery
of insulin increased the time plasma glucose levels were
in target by a median 15% (interquartile range 3-35%),
P=0.002. For the eating out scenario, closed loop
delivery increased the time plasma glucose levels were
in target by a median 28% (2-39%), P=0.01. Analysis of
pooled data showed that the overall time plasma
glucose was in target increased by a median 22% (337%) with closed loop delivery (P<0.001). Closed loop
delivery reduced overnight time spent hypoglycaemic
(plasma glucose ≤3.9 mmol/L) by a median 3% (0-20%),
P=0.04, and eliminated plasma glucose concentrations
below 3.0 mmol/L after midnight.
Conclusion
These two small crossover trials
suggest that closed loop delivery of
insulin may improve overnight control
of glucose levels and reduce the risk of
nocturnal hypoglycaemia in adults with
type 1 diabetes.
Trial registration ClinicalTrials.gov NCT00910767 and NCT00944619.
Message/Comments
1型糖尿病患者24人を対象に、夜間のクローズ
ドループ制御によるインスリン注入（人工膵
臓）の安全性、有効性を無作為化比較クロス
オーバー試験で検討。従来のインスリンポンプ
群に比べ、クローズドループ制御群で、全時間
血漿グルコース濃度が目標値（3.918.0mmol/L）内にあった時間の22％（中央値）
増加が見られた。
小児や思春期の対象者のデータは１年前に
Lancetに報告されたが今回は大人のデータ。
アルゴリズムが問題だが日本では．．．