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 2015 年 12 月 17 日 8:30-8:55 ８階 医局 Gunderson EP, Hurston SR, Ning X, Lo JC, Crites Y, Walton D, Dewey KG, Azevedo RA, Young S, Fox G, Elmasian CC, Salvador N, Lum M, Sternfeld B, Quesenberry CP Jr; Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy Investigators. Lactation and Progression to Type 2 Diabetes Mellitus After Gestational Diabetes Mellitus: A Prospective Cohort Study. Ann Intern Med. 2015 Nov 24:889-898. doi: 10.7326/M15-0807. Linnebjerg H1, Lam EC2, Seger ME3, Coutant D3, Chua L2, Chong CL2, Ferreira MM4, Soon D2, Zhang X3. Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies. Diabetes Care. 2015 Dec;38(12):2226-33. doi: 10.2337/dc14-2623. Epub 2015 Aug 25.

2. https://en.wikipedia.org/wiki/Kaiser_Permanente

3. From Kaiser Permanente Northern California and the Permanente Medical Group, Oakland, and University of California, Davis, Davis, California. Ann Intern Med. 2015 Dec 15;163(12):889-98. doi: 10.7326/M15-0807.

4. Background: Lactation improves glucose metabolism, but its role in preventing type 2 diabetes mellitus (DM) after gestational diabetes mellitus (GDM) remains uncertain. Objective: To evaluate lactation and the 2-year incidence of DM after GDM pregnancy.

5. Design: Prospective, observational cohort of women with recent GDM. (ClinicalTrials.gov: NCT01967030) Setting: Integrated health care system. Participants: 1035 women diagnosed with GDM who delivered singletons at 35 weeks' gestation or later and enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy from 2008 to 2011. Measurements: Three in-person research examinations from 6 to 9 weeks after delivery (baseline) and annual follow- up for 2 years that included 2-hour, 75-g oral glucose tolerance testing; anthropometry; and interviews. Multivariable Weibull regression models evaluated independent associations of lactation measures with incident DM adjusted for potential confounders.

6. DM = diabetes mellitus; GDM = gestational diabetes mellitus; KPNC = Kaiser Permanente Northern California; OGTT = oral glucose tolerance test; SWIFT = Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy. Figure. Study flow diagram.

7. Lactation intensity at 6 to 9 weeks after delivery (baseline) represents the cumulative amount of formula and breast milk fed since delivery and the intensity for the past 7 days (average number of breast milk– and formula-feeding episodes per 24 hours; quantity of formula per feeding; and total number of feedings per day, including water, other liquids, or solids). We classified women into 1 of the 4 following lactation intensity groups at 6 to 9 weeks after delivery: exclusive lactation (no formula, foods, or liquids), mostly lactation (>0 to 6 oz of formula per 24 hours), mostly formula (>17 oz per 24 hours) and mixed (7 to 17 oz of formula per 24 hours) or inconsistent lactation pattern, and exclusive formula feeding (formula only; no breastfeeding or breastfeeding <3 weeks) since birth. Women who transitioned into the mixed or inconsistent group after eligibility screening and before enrollment (n = 101) were classified as mostly formula feeding based on similar DM incidence.

15. Lactation increases energy expenditure (28) and mobilizes adipose stores in the femoral region and possibly visceral fat (29, 30). However, it has only slight effects on body composition and may have a minimal or no effect on postpartum weight loss, although evidence is mixed (9, 31–34). In our study, greater weight loss (1.0 to 1.3 kg) at 1 year after delivery for the exclusive or mostly lactation groups versus formula groups slightly mediated the association between lactation and lower DM incidence, although findings remained statistically significant.28293093134 Potential mechanisms to explain the lower incidence of DM with higher intensity and duration of lactation include preservation of pancreatic β cells (35), less inflammation, and improved endothelial function; however, biochemical evidence is sparse. The hormone prolactin is known to increase pancreatic β-cell mass and function during human pregnancy, but effects on β cells during the peripartum and postpartum periods have not been delineated.35 Prolactin also regulates adipogenesis to suppress lipid storage as well as release of the inflammatory cytokine, interleukin-6 (37), and adiponectin from adipocytes (38). In SWIFT, lower fasting plasma adiponectin and leptin levels were associated with higher lactation intensity at baseline.3738

16. The American Academy of Pediatrics recommends exclusive breastfeeding for approximately 6 months, followed by continued breastfeeding with complementary foods for 1 year or longer (44). International professional bodies have recommended breastfeeding for women with GDM but have acknowledged that evidence was insufficient to conclude that it conferred longer-term metabolic benefits for women (45). Currently, only 43% of U.S. women report exclusively breastfeeding at 3 months, and by 6 months, only 51% are breastfeeding at all (46). Breastfeeding promotion may be a practical, low-cost intervention during the postpartum period to prevent diabetes in high-risk women, with the potential for benefits that are complementary to lifestyle interventions targeting weight loss. Modification of lactation behaviors to increase intensity and duration should be considered a high priority for pregnant and postpartum women with GDM because of their lasting metabolic benefits. Greater allocation of health care resources to promote and support exclusive and extended breastfeeding may benefit high-risk women by reducing their risk for midlife progression to DM.444546

17. Results: Of 1010 women without diabetes at baseline, 959 (95%) were evaluated up to 2 years later; 113 (11.8%) developed incident DM. There were graded inverse associations for lactation intensity at baseline with incident DM and adjusted hazard ratios of 0.64, 0.54, and 0.46 for mostly formula or mixed/inconsistent, mostly lactation, and exclusive lactation versus exclusive formula feeding, respectively (P trend = 0.016). Time-dependent lactation duration showed graded inverse associations with incident DM and adjusted hazard ratios of 0.55, 0.50, and 0.43 for greater than 2 to 5 months, greater than 5 to 10 months, and greater than 10 months, respectively, versus 0 to 2 months (P trend = 0.007). Weight change slightly attenuated hazard ratios.

18. Limitation: Randomized design is not feasible or desirable for clinical studies of lactation. Conclusion: Higher lactation intensity and longer duration were independently associated with lower 2-year incidences of DM after GDM pregnancy. Lactation may prevent DM after GDM delivery. Primary Funding Source: National Institute of Child Health and Human Development.

19. Message 妊娠 35 週以降に単胎出産した妊娠糖尿病 （ GDM ）患者 1035 例を対象に、授乳状況と産 後の 2 型糖尿病（ DM ）発症率の関連を前向きコ ホート研究で検証。産後 2 年間追跡し得た 959 例 の DM 発症率は 11.8 ％だった。授乳の頻度およ び母乳栄養期間と DM 発症率には段階的な逆相関 が見られた（傾向の P ＝ 0.016 、 0.007 ）。 リスクほぼ半減！ http://www.m3.com/clinical/journal/16027

21. 1 Eli Lilly and Company, Indianapolis, IN 2 Lilly-NUS Centre for Clinical Pharmacology, Singapore 3 PAREXEL International Bloemfontein Early Phase Unit, Bloemfontein, South Africa

22. OBJECTIVE LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union– and US-approved versions of IGlar.

23. RESEARCH DESIGN AND METHODS These were three single-site, randomized, double-blind, two-treatment, four period, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ≥7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h.

25. For the two studies in which US-approved IGlar was administered (both of which were conducted in Singapore), subjects were required to be overtly healthy men or women, aged 21–65 years, with a BMI between 18.5 and 29.9 kg/m 2 and a fasting plasma glucose value <108 mg/dL (6.0 mmol/L). For the study comparing LY IGlar and EU-approved IGlar (conducted in South Africa), subjects were required to be overtly healthy men or women, aged 18–60 years, with a BMI between 18.5 and 32.0 kg/m 2, HbA1c levels ≤6.4% (46 mmol/mol), fasting plasma glucose levels ≤ 99 mg/dL (5.5 mmol/L), and a normal glucose tolerance. “Biosimilar” is a regulatory designation; LY IGlar may be designated as a biosimilar in some geographic regions (e.g., the European Union [EU]) and not in others (e.g., the US, where insulins are not classified as biologics)

26. Correction for endogenous insulin concentrations using C-peptide concentration data was performed based on Owens’ method (10) using the following equation: [LY IGlar or IGlar] ＝ [serum insulin] － F*[C-peptide] where F is the average of the ratios of serum insulin to C-peptide at baseline (where baseline was -30 and 0 min for the studies in which US-approved IGlar was administered and -60, -30, and 0 min for the study comparing LY IGlar with EU- approved IGlar).

27. Figure 2—Mean ± SD C- peptide–corrected serum insulin concentrations and GIRs after administration of 0.5 units/kg s.c. LY IGlar, EU-approved IGlar, or US-approved IGlar in three 2- treatment, 4-period, crossover design studies. A, C, and E: Plots of mean C- peptide–corrected insulin (LY IGlar or IGlar [Lantus]) concentration in the 24 h after 0.5 units/kg s.c. administration of three insulin glargine products. (A, C, and E are from 3 separate studies conducted in separate groups of subjects.) B, D, and F: Plots of mean glucose infusion rate, a measure of insulin action, in the 24 h after 0.5 units/kg s.c. administration of 3 insulin glargine products. (B, D, and F are from 3 separate studies conducted in separate groups of subjects.)

29. RESULTS A total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [Cmax]) and PD (maximum glucose infusion rate [Rmax]; total glucose infusion during the clamp [Gtot]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. Adverse events were similar between treatments.

30. CONCLUSIONS These studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

31. Message グラルギン BS とランタス 同等というデータ