1. Journal Club 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 2014 年 10 月 16 日 8:30-8:55 ８階 医局 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.

2. 第２巻 : 責任編集 松田昌文 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 医薬ジャーナル社

3. http://dx.doi.org/10.1016/S0140-6736(14)61639-1

4. www.thelancet.com Published online September 24, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61183-1

5. 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-hydroxy- 3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

6. 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 meta- analysis. These findings were compared with a meta- analysis 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.

7. 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.

8. 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.

10. 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.

14. 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 intensive- dose vs moderate dose trials).

15. 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.

16. 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 ）。

19. 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.

20. 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.

21. Low risk lifestyle factors include maintaining healthy body weight, consuming healthy diet, regular exercise, and not smoking.

26. 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

27. 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.

28. 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.

29. 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！？