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Journal Club. Zinman B, Fulcher G, Rao PV, Thomas N, Endahl LA, Johansen T, Lindh R, Lewin A, Rosenstock J, Pinget M, Mathieu C .

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Journal club

Journal Club

ZinmanB, Fulcher G, Rao PV, Thomas N, Endahl LA, Johansen T, Lindh R, Lewin A, Rosenstock J, Pinget M, Mathieu C.

Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial.

Lancet. 2011 Mar 12;377(9769):924-31.

GrevingJ, Visseren F, de Wit G, Algra A.

Statin treatment for primary prevention of vascular disease: whom to treat? Cost-effectiveness analysis.

BMJ. 2011 Mar 30;342:d1672. doi: 10.1136/bmj.d1672.

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

2011年4月14日8:30-8:55

8階 医局


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Insulin degludec

http://www.novonordisk.com/press/photo_library


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Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada (Prof B Zinman MD); Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia (Prof G Fulcher MD); Nizam’s Institute of Medical Sciences University, Hyderabad, India (Prof P V Rao MD); Christian Medical College, Vellore, India (Prof N Thomas FRCP); Novo Nordisk, Soeborg, Denmark (L A Endahl PhD, T Johansen MD, R Lindh PhD); National Research Institute, Los Angeles, CA, USA (A Lewin MD); Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA (Prof J Rosenstock MD); University Hospital Strasbourg, Strasbourg, France (Prof M Pinget MD); and UZ GasthuisbergKatholiekeUniversiteit Leuven, Leuven, Belgium (Prof C Mathieu MD)

Lancet 2011; 377: 924–31


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Background

Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. This study aimed to assess efficacy and safety of insulin degludec injected once a day or three times a week compared with insulin glargine once a day in insulin-naive people with type 2 diabetes, who were inadequately controlled with oral antidiabetic drugs.


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Methods

In this 16-week, randomised, open-label, parallel-group phase 2 trial, participants aged 18–75 years with type 2 diabetes and glycosylated haemoglobin (HbA1C) of 7・0–11・0% were enrolled and treated at 28 clinical sites in Canada, India, South Africa, and the USA. Participants were randomly allocated in a 1:1:1:1 ratio by computer generated block randomisation to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA1C after 16 weeks of treatment. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00611884.


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Before Randomisation

Before trial entry, participants had to be insulin-naive and have been treated with one or two oral antidiabetic drugs (metformin, α-glucosidase inhibitors, sulphonylurea, or meglitindes) for more than 2 months at stable half-maximum to maximum allowed doses. Patients were excluded if they were treated with thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or other interventions that could interfere with glucose metabolism within 3 months of the start of the trial.

Before randomisation, eligible participants discontinued their pretrial oral antidiabetic drug treatment and underwent a 2-week forced metformin-titration period (dose increased to 2000 mg per day; 1000 mg at breakfast and evening meal), which was followed up by a 1-week metformin maintenance period. Patients were eligible for randomisation if the maximum metformin dose (2000 mg) or maximum-tolerated dose (1500 mg) per day remained unchanged in the maintenance period, and if the median before-breakfast self-monitored blood glucose value (measured on 3 consecutive days immediately before randomisation) was 7・5 mmol/L (135 mg/dl) or more.


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insulin degludec (Novo Nordisk, Bagsvaerd, Denmark) three times a week (900 nmol/mL formulation, dosed in the evening on Monday, Wednesday, and Friday),

insulin degludec group A (600 nmol/mL formulation) once a day,

insulin degludec group B (900 nmol/mL formulation) once a day, or

insulin glargine (600 nmol/mL formulation; Sanofi -Aventis, Paris, France) once a day, all in combination with metformin.

100U/mL


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Figure 2: Mean HbA1C and plasma glucose concentrations by trial intervention

(A) Mean HbA1C. (B) Mean fasting plasma glucose. (C) Mean nine-point self monitored blood glucose profiles. Data are reported mean values from all randomised participants. Last observation carried forward is used for each timepoint in A and B. Plasma-calibrated values are shown in C. IDeg 3TW=insulin degludec three times a week. IDeg OD(A)=insulin degludec (group A) once a day. IDeg OD(B)=insulin degludec (group B) once a day. IGlar=insulin glargine once a day.


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180 mg/dl

126 mg/dl

Figure 2: Mean HbA1C and plasma glucose concentrations by trial intervention

(A) Mean HbA1C. (B) Mean fasting plasma glucose. (C) Mean nine-point selfmonitored blood glucose profiles. Data are reported mean values from all randomised participants. Last observation carried forward is used for each timepoint in A and B. Plasma-calibrated values are shown in C. IDeg 3TW=insulin degludec three times a week. IDeg OD(A)=insulin degludec (group A) once a day. IDeg OD(B)=insulin degludec (group B) once a day. IGlar=insulin glargine once a day.


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Webappendix table 2: Hypoglycaemic episodes – ADA classification


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Interpretation

Physiological replacement of insulin in diabetes is challenging and remains an elusive goal, as evidenced by the many patients who do not achieve recommended treatment targets. In basal insulin replacement, the presently used insulin analogues glargine and determir have some advantages over human neutral protamine hagedorn insulin. Insulin degludec has a half-life longer than 24 h and was developed to provide a more appropriate basal pharmacokinetic profi le. In this proof-of-concept phase 2 study in patients with type 2 diabetes, insulin degludec provided much the same glycaemic control as did insulin glargine when injected once a day. Because of its ultra-long action profile, insulin degludec could also be injected three-times weekly and still provide comparable glycaemic control to insulin glargine once a day. This new basal insulin analogue might be a valuable addition to clinical practice.


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Findings

Of 367 patients screened, 245 were eligible for inclusion. 62 participants were randomly allocated to receive insulin degludec three times a week (starting dose 20 U per injection [1 U=9 nmol]), 60 to receive insulin degludec once a day (starting dose 10 U [1 U=6 nmol]; group A), 61 to receive insulin degludec once a day (starting dose 10 U [1 U=9 nmol]; group B), and 62 to receive insulin glargine (starting dose 10 U [1 U=6 nmol]) once a day. At study end, mean HbA1C levels were much the same across treatment groups, at 7・3% (SD 1・1), 7・4% (1・0), 7・5% (1・1), and 7・2% (0・9), respectively. Estimated mean HbA1C treatment differences from insulin degludec by comparison with insulin glargine were 0・08% (95% CI –0・23 to 0・40) for the three dose per week schedule, 0・17% (–0・15 to 0・48) for group A, and 0・28% (–0・04 to 0・59) for group B. Few participants had hypoglycaemiaand the number of adverse events was much the same across groups, with no apparent treatment specific pattern.


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Interpretation

Insulin degludec provides comparable glycaemic control to insulin glargine without additional adverse events and might reduce dosing frequency due to its ultra-long action profile.

Funding

Novo Nordisk.


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Message/Comments

2型糖尿病患者245人を対象に、超持効型新基礎インスリン製剤insulin degludecの有効性を無作為化比較試験で検討。インスリングラルギン1日1回とinsulin degludec週3回または1日1回で比較したところ、両剤で同等の血糖コントロールが認められた。また有害事象も同等だったことから、投与回数減少の可能性を著者らは示唆している。

低血糖が増えないとよいのですが...


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30

4S - Placebo

25

Rx - Statin therapy

PRA – pravastatin

ATV - atorvastatin

Secondary Prevention

4S - Rx

20

Event rate (%)

LIPID - Placebo

15

CARE - Placebo

LIPID - Rx

CARE - Rx

Primary Prevention

HPS - Placebo

HPS - Rx

TNT – ATV10

10

PROVE-IT - PRA

WOSCOPS – Placebo

TNT – ATV80

PROVE-IT – ATV

AFCAPS - Placebo

6

5

AFCAPS - Rx

WOSCOPS - Rx

ASCOT - Placebo

ASCOT - Rx

0

40

(1.0)

60

(1.6)

80

(2.1)

100

(2.6)

120

(3.1)

140

(3.6)

160

(4.1)

180

(4.7)

200

(5.2)

LDL-C achieved mg/dL (mmol/L)

LDL-Cholesterol and Coronary event rate

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

LaRosa JC et al. N Engl J Med 2005;352:1425-1435


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スタチン介入大規模臨床試験におけるLDL-Cと冠動脈疾患イベント発症率の関係

4S DM (placebo)

Diabetes secondary

Secondary prevention

Primary prevention

30

CARE DM (placebo)

4S DM (simvastatin)

LIPID DM (placebo)

20

4S (placebo)

LIPID DM (pravastatin)

20

CARE DM (pravastatin)

4S (simvastatin)

Patient with CHD event(mean%)

LIPID (placebo)

15

CARE (placebo)

WOSCOPS (placebo)

10

CARE (pravastatin)

WOSCOPS (pravastatin)

LIPID (pravastatin)

5

AFCAPS (lovastatin)

AFCAPS (placebo)

0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

154

58

77

116

193

Mean LDL cholesterol( mmol / l )(mg/dl)

Fisher M:Heart,90(3),336-340(2004)


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1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands

2Department of Vascular Medicine, University Medical Center Utrecht

3Center for Prevention and Health Services Research, National Institute of Public Health and the Environment, Bilthoven, Netherlands

4Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht

BMJ 2011;342:d1672

doi:10.1136/bmj.d1672


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Objective

To assess the cost-effectiveness of low dose statins for primary prevention of vascular disease, incorporating current prices, non-adherence (reduced clinical efficacy while maintaining healthcare costs), and the results of the recently published JUPITER trial.


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Design Cost-effectiveness analysis using a Markov model. Sensitivity analyses and Monte Carlo simulation evaluated the robustness of the results.

SettingPrimary care in The Netherlands.

ParticipantsHypothetical populations of men and women aged 45 to 75 years without a history of vascular disease at different levels of risk for vascular disease (myocardial infarction and stroke) over 10 years.

InterventionsLow dose statin treatment daily versus no treatment for 10 years.

Main outcome measures Number of fatal and nonfatal vascular events prevented, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios over 10 years.


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Fig 1 General structure of the Markov model.

People enter the model while taking statins or not and can progress from healthy to one of the other health states (shaded boxes), including death, in each cycle. Those who have statin related adverse effects (myopathy and rhabdomyolysis) stop taking statins. MI=myocardial infarction


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QALYs were calculated by multiplying the time a person remained in a certain health state by the utility associated with that particular health state and subsequent summing up over all health states

ICER=incremental cost effectiveness ratio Euro(cost) / QALY


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ICER=incremental cost effectiveness ratio


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Fig 3 |Probabilistic sensitivity analysis and cost-effectiveness acceptability curve.

Top: results of probabilistic sensitivity analysis for base case of 55 year old men (10-year vascular risk of 10%). Each dot represents 1 iteration of the model. Y axis represents incremental costs of statins compared with no therapy. X axis represents incremental QALYs with statins compared with no therapy. Diagonal lines represent a cost per QALY gained of €20000 and of €80000.

Below: Y axis represents probability that the cost per QALY gained is less than or equal to values on X axis.

ICER=incremental cost effectiveness ratio


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Results

Over a 10-year period, statin treatment cost €35 000 (£30 000, $49 000) per QALY gained for men aged 55 years with a 10-year vascular risk of 10%. The incremental cost-effectiveness ratio improved as risk for vascular disease increased. The cost per QALY ranged from approximately €5000 to €125 000 when the 10-year vascular risk for men aged 55 years was varied from 25% to 5%. The incremental cost-effectiveness ratio slightly decreased with age after the level of vascular risk was specified. Results were sensitive to the costs of statin treatment, statin effectiveness, non-adherence, disutility of taking medication daily, and the time horizon of the model.


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Conclusions

In daily practice, statin treatment seemed not to be cost-effective for primary prevention in populations at low risk of vascular disease, despite low costs of generic drug pills.

Adherence to statin treatment needs to be improved to enhance the cost-effectiveness of the use of statins for primary prevention.


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Message/Comments

血管病歴のない45-75歳の仮説母集団を対象に、血管病の一次予防における低用量スタチンの費用対効果をマルコフモデルで検討。10年リスク10%の55歳男性における質調整生存年あたりの費用は3万5000ユーロで、リスクが高いほど増分費用効果比は向上した(同リスク25%で5000ユーロ、5%で12万5000ユーロ)。

効果を上げるにはきちんと服用?


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