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/S0140-
6736(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
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

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 moderatedose 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.

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.

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 (nonsmoker, ≥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.

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 ！？