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Swerdlow DI et al:
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight:
evidence from genetic analysis and randomised trials.
Lancet. 2014 Sep 24. pii: S0140-6736(14)61183-1. doi: 10.1016/S01406736(14)61183-1.
Zhang C, Tobias DK, Chavarro JE, Bao W, Wang D, Ley SH, Hu FB.
Adherence to healthy lifestyle and risk of gestational diabetes mellitus:
prospective cohort study.
BMJ. 2014 Sep 30;349:g5450. doi: 10.1136/bmj.g5450.
2014年10月16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
第２巻:責任編集松田昌文
医薬ジャーナル社
薬物療法の実践
～血糖降下薬を中心に～
SGLT-2阻害薬！ TZD薬！ DPP-4阻害薬
血糖管理の「維持療法」
GLP-1受容体作動薬自己注射指導
http://dx.doi.org/10.1016/S0140-6736(14)61639-1
www.thelancet.com Published online September 24, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61183-1
Background
Statins increase the risk of new-onset
type 2 diabetes mellitus. We aimed to
assess whether this increase in risk is a
consequence of inhibition of 3-hydroxy3-methylglutaryl-CoA reductase
(HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the
HMGCR gene, rs17238484 (for the main analysis)
and rs12916 (for a subsidiary analysis) as proxies for
HMGCR inhibition by statins. We examined
associations of these variants with plasma lipid,
glucose, and insulin concentrations; bodyweight;
waist circumference; and prevalent and incident type
2 diabetes. Study-specific effect estimates per copy
of each LDL-lowering allele were pooled by metaanalysis. These findings were compared with a metaanalysis of new-onset type 2 diabetes and
bodyweight change data from randomised trials of
statin drugs. The effects of statins in each
randomised trial were assessed using meta-analysis.
Figure 1: Association of rs17238484 genotype with type-2 diabetes-related traits
Association of the rs17238484 genotype with (A) major plasma lipids fractions; (B) plasma glucose and insulin; (C)
BMI and bodyweight; (D) waist and hip circumference and waist:hip ratio; and (E) risk of type 2 diabetes. Bars are
95% CIs. BMI=body-mass index.
Figure 1: Association of rs17238484 genotype with type-2 diabetes-related traits
Association of the rs17238484 genotype with (A) major plasma lipids fractions; (B) plasma glucose and insulin; (C)
BMI and bodyweight; (D) waist and hip circumference and waist:hip ratio; and (E) risk of type 2 diabetes. Bars are
95% CIs. BMI=body-mass index.
Figure 2: Meta-analyses of the associations of 3-hydroxy-3-methylglutaryl-CoA reductase variants
rs17238484 and rs12916 with risk of type 2 diabetes
Data were analysed by fi xed-eff ects meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies.
Each additional rs17238484-G allele was associated with a mean 0·06
mmol/L (95% CI 0·05—0·07) lower LDL cholesterol and higher body weight
(0·30 kg, 0·18—0·43), waist circumference (0·32 cm, 0·16—0·47), plasma
insulin concentration (1·62%, 0·53—2·72), and plasma glucose
concentration (0·23%, 0·02—0·44). The rs12916 SNP had similar effects on
LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G
allele seemed to be associated with higher risk of type 2 diabetes (odds
ratio [OR] per allele 1·02, 95% CI 1·00—1·05); the rs12916-T allele
association was consistent (1·06, 1·03—1·09). In 129 170 individuals in
randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI
0·18—1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95%
CI 0·10—0·38 in all trials; 0·33 kg, 95% CI 0·24—0·42 in placebo or
standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in
intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9—
6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR
1·12, 95% CI 1·06—1·18 in all trials; 1·11, 95% CI 1·03—1·20 in placebo or
standard care controlled trials and 1·12, 95% CI 1·04—1·22 in intensivedose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted
with statins is at least partially explained by
HMGCR inhibition.
Funding
The funding sources are cited at the end of
the paper.
Message
スタチンによる3-ヒドロキシ-3-メチルグルタリ
ルCoA還元酵素（HMGCR）阻害と2型糖尿病（DM）
リスクの関連を、遺伝子解析43件（被験者約22
万人）と無作為化試験のデータから検証。HMGCR
遺伝子の一塩基変異多型rs17238484-Gアレルと
DMリスク増加との関連が疑われた（1アレル当た
りオッズ比1.02）。
Objective To quantify the association
between a combination of healthy lifestyle
factors before pregnancy (healthy body
weight, healthy diet, regular exercise, and
not smoking) and the risk of gestational
diabetes.
Design Prospective cohort study.
Setting Nurses’ Health Study II, United
States.
Participants 20 136 singleton live births in
14 437 women without chronic disease.
Main outcome measure Self reported
incident gestational diabetes diagnosed by
a physician, validated by medical records in
a previous study.
Low risk lifestyle factors include
• maintaining healthy body weight,
consuming healthy diet,
• regular exercise, and
• not smoking.
Association between number of low risk lifestyle factors and risk of gestational
diabetes. Low risk lifestyle factors include maintaining healthy body weight,
consuming healthy diet, regular exercise, and not smoking. Relative risk adjusted
for age, parity, family history of diabetes, history of infertility, race/ethnicity,
questionnaire period, total energy intake, and alcohol consumption No
Results Incident first time gestational diabetes was reported in 823
pregnancies. Each lifestyle factor measured was independently and
significantly associated with risk of gestational diabetes. The
combination of three low risk factors (non-smoker, ≥150 minutes a week
of moderate to vigorous physical activity, and healthy eating (top two
fifths of Alternate Healthy Eating Index-2010 adherence score)) was
associated with a 41% lower risk of gestational diabetes compared with
all other pregnancies (relative risk 0.59, 95% confidence interval 0.48 to
0.71). Addition of body mass index (BMI) <25 before pregnancy (giving
a combination of four low risk factors) was associated with a 52% lower
risk of gestational diabetes compared with all other pregnancies (relative
risk 0.48, 0.38 to 0.61). Compared with pregnancies in women who did
not meet any of the low risk lifestyle factors, those meeting all four
criteria had an 83% lower risk of gestational diabetes (relative risk 0.17,
0.12 to 0.25). The population attributable risk percentage of the four risk
factors in combination (smoking, inactivity, overweight, and poor diet)
was 47.5% (95% confidence interval 35.6% to 56.6%). A similar
population attributable risk percentage (49.2%) was observed when the
distributions of the four low risk factors from the US National Health and
Nutrition Examination Survey (2007-10) data were applied to the
calculation.
Conclusions Adherence to a low risk
lifestyle before pregnancy is associated with
a low risk of gestational diabetes and could
be an effective strategy for the prevention of
gestational diabetes.
Message
Nurses’Health Study IIにおいて慢性疾患のな
い女性1万4437人の出産2万136件を対象に、生活
習慣と妊娠糖尿病リスクとの関連を前向きコ
ホート研究で検討。低リスク因子（非喫煙、運
動、健康的食事）は妊娠糖尿病リスク41％低下
と関連し、妊娠前BMI25未満を追加すると52％の
低下と関連した（相対リスク0.48）。
リスク因子でなく低リスクの因子で解析して
ある。介入というわけにはゆかないが、妊娠予
定であれば生活習慣を日ごろから注意！？

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