Transcript 20140925metaGLP1raPlusInsulin

Journal Club
Eng C, Kramer CK, Zinman B, Retnakaran R.
Glucagon-like peptide-1 receptor agonist and basal insulin combination
treatment for the management of type 2 diabetes: a systematic review
and meta-analysis.
Lancet. 2014 Sep 11. pii: S0140-6736(14)61335-0. doi: 10.1016/S01406736(14)61335-0. [Epub ahead of print]
2014年9月25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
a
Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON, Canada
b Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON,
Canada
c Division of Endocrinology, University of Toronto, Toronto, ON, Canada
Lancet. 2014 Sep 11. pii: S0140-6736(14)61335-0. doi: 10.1016/S0140-6736(14)61335-0.
Background
Combination treatment with a glucagon-like
peptide-1 (GLP-1) agonist and basal insulin has
been proposed as a treatment strategy for type 2
diabetes that could provide robust glucoselowering capability with low risk of hypoglycaemia
or weight gain. We thus did a systematic review
and meta-analysis of randomised controlled trials
to assess the effect of this combination treatment
on glycaemic control, hypoglycaemia, and weight
gain in patients with type 2 diabetes.
Methods
We systematically searched PubMed, Embase,
Cochrane, Web of Knowledge, FDA.gov, and
ClinicalTrials.gov for randomised controlled trials
(published between Jan 1, 1950, and July 29,
2014; no language restrictions) comparing GLP-1
agonist and basal insulin combination treatment
to other anti-diabetic treatments. Our main
endpoints were glycaemic control, hypoglycaemia,
and change in weight. We assessed pooled data
by use of a random-effects model.
Figure 1:
Study selection process
Outcomes assessed are: (A) HbA1c
Figure 2: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing HbA1c concentrations For each estimate, the grey shaded area is the weight of the estimate in proportion to the overall effect.
Outcomes assessed are: (B) HbA1c (%) in studies
that compared combination treatment with basalbolus insulin treatment
Figure 2: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing HbA1c concentrations For each estimate, the grey shaded area is the weight of the estimate in proportion to the overall effect.
Outcomes assessed are: (C) proportion of participants
with HbA1c ≤7・0% at the end of intervention
Figure 2: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing HbA1c concentrations For each estimate, the grey shaded area is the weight of the estimate in proportion to the overall effect.
Outcomes assessed are: (D) proportion of participants with HbA1c ≤7・0% at
the end of intervention in studies that compared combination treatment with
basal-bolus insulin treatment.
Figure 2: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing HbA1c concentrations For each estimate, the grey shaded area is the weight of the estimate in proportion to the overall effect.
Outcomes assessed are (A) hypoglycaemia
Figure 3: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing hypoglycaemia and change in weight For each estimate, the grey shaded area is the weight of the estimate in proportion to the
overall effect.
Outcomes assessed are (B) hypoglycaemia in studies that compared
combination treatment with basal-bolus insulin treatment
Figure 3: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing hypoglycaemia and change in weight For each estimate, the grey shaded area is the weight of the estimate in proportion to the
overall effect.
Outcomes assessed are (C) change in weight (kg) at the end of intervention
Figure 3: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing hypoglycaemia and change in weight For each estimate, the grey shaded area is the weight of the estimate in proportion to the
overall effect.
Outcomes assessed are (D) change in weight (kg) at the end of intervention in
studies that compared combination treatment with basal-bolus insulin
treatment.
Figure 3: Meta-analyses of glucagon-like peptide-1 (GLP-1) agonist and basal insulin combination treatment versus other anti-diabetic
treatments, comparing hypoglycaemia and change in weight For each estimate, the grey shaded area is the weight of the estimate in proportion to the
overall effect.
メタアナリシス論文の中に頻出するfunnel plotをどう読むか。
funnel plotとはメタアナリシス中で偏った論文が集められていないかを検証するための方法。
図の中央の実線がメタアナリシスで得られたORを示している。縦軸が標準偏差の大きさを示す。
なので、サンプルサイズが大きくて標準偏差が小さい研究ほど上側に分布、小規模研究ほど下側に分布
する。
論文が偏りなく集められているとすると、サンプリングエラーだけが残るので通常は中央の実線から対称
性に論文が散らばるはずである。
逆に片方の介入に都合のいい論文だけを集めているとプロットが非対称性になってしまう。
なので、funnel plotをおこなって左右対称にプロットされていればpublication biasなど受けずに適切に論
文収集がおこなわれているという証明になる。
それを数字で表したのがEgger's test。これは対称に分布しているという帰無仮説と非対称に分布してい
るという対立仮説を用いて疫学的に対称性を証明する手法。
まぁ要するにp値が0.05以上だと対称性分布っぽいなぁと言える。
（もっとちゃんと言うと、5%を有意とした検定において対称性分布であるという帰無仮説を棄却できない）
以上からもわかるようにfunnel plotはある程度のプロット数がないと対称かどうかわからなくなってしまう。
通常は10以上の論文が集められている前提で使われる手法である。
(BMJ 2013; 346: f1342)
Findings
Of 2905 identified studies, 15 were eligible and were
included in our analysis (N=4348 participants). Compared
with other anti-diabetic treatments, GLP-1 agonist and basal
insulin combination treatment yielded an improved mean
reduction in glycated haemoglobin (HbA1c) of −0·44% (95%
CI −0·60 to −0·29), an improved likelihood of achieving the
target HbA1c of 7·0% or lower (relative risk [RR] 1·92; 95%
CI 1·43 to 2·56), no increased relative risk of hypoglycaemia
(0·99; 0·76 to 1·29), and a mean reduction in weight of −3·22
kg (−4·90 to −1·54). Furthermore, compared with basal-bolus
insulin regimens, the combination treatment yielded a mean
reduction in HbA1c of −0·1% (−0·17 to −0·02), with lower
relative risk of hypoglycaemia (0·67, 0·56 to 0·80), and
reduction in mean weight (−5·66 kg; −9·8 to −1·51).
Interpretation
GLP-1 agonist and basal insulin combination
treatment can enable achievement of the ideal
trifecta in diabetic treatment: robust glycaemic
control with no increased hypoglycaemia or
weight gain. This combination is thus a potential
therapeutic strategy that could improve the
management of patients with type 2 diabetes.
Message
2型糖尿病（DM）管理におけるグルカゴン様ペプ
チド-1（GLP-1）受容体作動薬＋基礎インスリン
併用療法の効果を、無作為化比較試験15件（被
験者4348人）のシステマティックレビューとメ
タ解析で検証。他の治療法に比べ併用療法で
HbA1cの平均低下値と7.0％未満達成率が改善し、
低血糖リスクや体重の増加は見られなかった。
このままゆくと、超速効型インスリンの売り上
げが減る？