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Vitamin D Supplementation and Type 2 Diabetes Prevention - A Randomized Controlled Trial

This study investigates the effect of vitamin D supplementation on the risk of developing type 2 diabetes in individuals with prediabetes. The trial aims to determine whether vitamin D supplementation can lower the risk of diabetes in this population.

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Vitamin D Supplementation and Type 2 Diabetes Prevention - A Randomized Controlled Trial

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  1. Journal Club Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, Brodsky I, Ceglia L, Chadha C, Chatterjee R, Desouza C, Dolor R, Foreyt J, Fuss P, Ghazi A, Hsia DS, Johnson KC, Kashyap SR, Kim S, LeBlanc ES, Lewis MR, Liao E, Neff LM, Nelson J, O'Neil P, Park J, Peters A, Phillips LS, Pratley R, Raskin P, Rasouli N, Robbins D, Rosen C, Vickery EM, Staten M; D2d Research Group. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019 Jun 7. doi: 10.1056/NEJMoa1900906. Chen HM, Yang YH, Chen KJ, Lee Y, McIntyre RS, Lu ML, Lee YC, Hsieh MC, Chin-Hung Chen V. Antidepressants reduced risk of mortality in patients with diabetes mellitus: a population-based cohort study in Taiwan. J Clin Endocrinol Metab. 2019 Jul 2. pii: jc.2018-02362. doi: 10.1210/jc.2018-02362. Trinh B, Donath MY, Läubli H. Successful Treatment of Immune Checkpoint Inhibitor-Induced Diabetes Mellitus With Infliximab. Diabetes Care. 2019 Jul 15. pii: dc190908. doi: 10.2337/dc19-0908. 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 2019年7月18日　8:30-8:55 ４階　カンファレンス室

  2. Tufts Medical Center (A.G.P., L.C., P.F., J.N., E.M.V.), the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (B.D.-H.), Brigham and Women’s Hospital (V.R.A.), and Harvard School of Public Health (J.H.W.), Boston, and the Spaulding Rehabilitation Network, Charlestown (P.S.) — all in Massachusetts; National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ (W.C.K.); the Maine Medical Center (I.B.) and the Maine Medical Center Research Institute (C.R.) — both in Scarborough; HealthPartners Institute, Minneapolis (C.C.); Duke University Medical Center, Durham, NC (R.C., R.D.); the University of Nebraska Medical Center and Omaha Veterans Affairs Medical Center, Omaha (C.D.); Baylor College of Medicine, Houston (J.F.), and the University of Texas Southwestern Medical Center, Dallas (P.R.) — both in Texas; MedStar Good Samaritan Hospital, Baltimore (A.G.), MedStar Health Research Institute, Hyattsville (J.P.), and the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (M.S.) — all in Maryland; Pennington Biomedical Research Center, Baton Rouge, LA (D.S.H.); the University of Tennessee Health Science Center, Memphis (K.C.J.); Cleveland Clinic, Cleveland (S.R.K.); Stanford University Medical Center, Stanford (S.K.), and the Keck School of Medicine of the University of Southern California, Los Angeles (A.P.) — both in California; Kaiser Permanente Center for Health Research–Northwest, Portland, OR (E.S.L.); the University of Vermont, Burlington (M.R.L.); Northwell Health Lenox Hill Hospital, New York (E.L.); Northwestern University, Chicago (L.M.N.); the Medical University of South Carolina, Charleston (P.O.); Emory University School of Medicine, Atlanta, and the Atlanta Veterans Affairs Medical Center, Decatur — both in Georgia (L.S.P.); AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, FL (R.P.); the University of Colorado Denver and the Veterans Affairs Eastern Colorado Health Care System, Denver (N.R.); and the University of Kansas Medical Center, Kansas City (D.R.). N Engl J Med. 2019 Jun 7. doi: 10.1056/NEJMoa1900906.

  3. Background Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown.

  4. Methods We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508.

  5. Figure 1. Screening, Randomization, and Follow-up. One participant in the vitamin D group was withdrawn administratively after a clinical site closed down early in the trial. Protocol-specified adverse events that led to discontinuation of the trial pills were hypercalcemia, a fasting urine calcium:creatinine ratio of more than 0.375, a low estimated glomerular filtration rate, and nephrolithiasis. Of the 2423 participants who underwent randomization, 14 (9 in the vitamin D group and 5 in the placebo group) were subsequently found not to meet all eligibility criteria. participants were askedto limit calcium supplements to 600 mg per day.

  6. There was no significant difference between the two groups in the use of outside-of-trial calcium supplements above the trial limit.

  7. Results A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (0.95% confidence interval, 0.75 to 1.04; P=0.12). The incidence of adverse events did not differ significantly between the two groups.

  8. Conclusions Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.)

  9. Message 糖尿病高リスク者へのビタミンDで発症リスク低下せず 2型糖尿病高リスク者2423例を対象に、ビタミンD補給（ビタミンD3 4000 IU/日）による糖尿病リスク低下作用を事象観察型試験で検討。ベースラインの血清25-ヒドロキシビタミンD濃度は不問とした。 　追跡期間中央値2.5年後、主要転帰に規定した糖尿病発症はビタミンD補給群293件、プラセボ群323件だった（100人年当たり9.39、10.66）。プラセボ群と比べ、ビタミンD群の糖尿病発症ハザード比は0.88（95％CI 0.75-1.04、P＝0.12）で、ビタミンDによって糖尿病リスクが有意に低下することはなかった。有害事象の発現率は両群で有意な差がなかった。 Negative dataだがNEJMでよく論文化されたと．．．　BMI低値とカルシウムで差があるようだが https://www.m3.com/clinical/journal/20498

  10. https://cocoromi-cl.jp/knowledge/psychiatry-medicine/antidepressant/about-antidepressant/https://cocoromi-cl.jp/knowledge/psychiatry-medicine/antidepressant/about-antidepressant/ https://www.psychiatrictimes.com/cme/antidepressants-part-1-100-years-and-counting/page/0/4

  11. ノルアドレナリン神経におけるモノアミン酸化酵素阻害薬の作用機序。ノルアドレナリン神経におけるモノアミン酸化酵素阻害薬の作用機序。 https://ja.wikipedia.org/wiki/%E3%83%A2%E3%83%8E%E3%82%A2%E3%83%9F%E3%83%B3%E9%85%B8%E5%8C%96%E9%85%B5%E7%B4%A0%E9%98%BB%E5%AE%B3%E8%96%AC

  12. Hong-Ming Chen, MDa,b, Yao-Hsu Yang, MD, PhDc,d, Ko-Jung Chen, MSd, Yena Lee, HBSce, Roger S. McIntyre, MD, PhDe, Mong-Liang Lu, MD, MSf, Yi-Chen Lee, OTR, PhDa, Ming-Chia Hsieh, MD, PhDg,h,i, Vincent Chin-Hung Chen, MD, PhDa,b* aDepartment of Psychiatry, Chang Gung Medical Foundation, Chiayi Chang Gung Memorial Hospital, Taiwan bDepartment of Psychiatry, Chang Gung University, Taiwan cDepartment for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi dHealth Information and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chia-yi Branch eDepartment of Psychiatry, University of Toronto, Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada fDepartment of Psychiatry, Wan-Fang Hospital & School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan gGraduate institute of integrated medicine, China medical university, Taiwan hDepartment of internal medicine, China medical university hospital, Taiwan iDepartment of Internal Medicine, Changhua Christian Hospital, Taiwan J Clin Endocrinol Metab. 2019 Jul 2. pii: jc.2018-02362. doi: 10.1210/jc.2018-02362.

  13. Context The effect of antidepressants (ATDs) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied although co-morbid depression is common in this population. Objective To explore the impact of ATDs on mortality among DM patients.

  14. Design A retrospective cohort study in a national database. Setting This population-based study used National Health Insurance Research Database in Taiwan. Since 2000, we identified 53,412 cases of newly diagnosed patients with DM and depression. Patient cases were followed for assessing mortality until 2013. Main outcome measure The association between mortality and ATDs use was explored adjusting for cumulative dosing.

  15. Figure 1. Flowchart of the study design

  16. Table 1. The demographic and clinical characteristics of cases ATD and non-ATD user ESRD=end-stage renal disease, COPD=Chronic Obstructive Pulmonary Disease, DCSI=Diabetes Complications Severity Index The median annual earnings for employees in Taiwan in 2017 was NT$470000 (US$15238) (http://focustaiwan.tw/news/aeco/201812240025.aspx)

  17. Table 2. Time-dependent Cox regression analysis of mortality in patients with DM and depressive disorder ESRD=end-stage renal disease, COPD=Chronic Obstructive Pulmonary Disease, DCSI=Diabetes Complications Severity Index *Adjustment for gender, age, urbanization, income, comorbidities, adapted DCSI

  18. Table 3. Time-dependent Cox regression analysis of mortality in patients with DM and depressive disorder: specific antidepressant subgroup analysis SSRI=selective serotonin reuptake inhibitors, SNRI=serotonin-norepinephrine reuptake inhibitors, NDRI=norepinephrine-dopamine reuptake inhibitors, RIMA=reversible inhibitor of monoamine oxidase A) *Adjustment for 7 types of ATDs, age, gender, urbanization, income, comorbidities, adapted Diabetes Complications Severity Index.

  19. Figure 2. The incidence rate of death per 100,000 person-years between three exposure subgroups (Time-fixed Model)

  20. Result Using the time-dependent Cox regression model, ATDs use was associated with significantly reduced mortality among patients with DM (in the highest dose group, hazard ratio [HR]= 0.65, 95% confidence interval [CI]= 0.59-0.71). Further analysis showed that differences on mortality existed across ATD categories: selective serotonin reuptake inhibitors (HR=0.63, 95% CI= 0.56-0.71), serotonin-norepinephrine reuptake inhibitors (HR=0.58, 95% CI= 0.44-0.78), norepinephrine-dopamine reuptake inhibitors (HR=0.20,95% CI= 0.07-0.63), mirtazapine (HR=0.60, 95% CI= 0.45-0.82), tricyclic/tetracyclic antidepressants (HR=0.73, 95% CI= 0.54-0.97), trazodone (HR=0.52, 95% CI= 0.29-0.91). However, reversible inhibitor of monoamine oxidase A (RIMA) was found to be associated with an increase, rather than decrease, in total mortality. (HR=1.48, 95% CI= 1.09-1.99).

  21. Conclusion Most ATDs but not RIMA were associated with significantly reduced mortality among population with comorbid DM and depression.

  22. Message 2000年以降に新たに糖尿病とうつ病を診断された、1型糖尿病と2型糖尿病を含む5万3,412人の台湾人を対象に行われた。調査は抗うつ治療の成果を調べるため2013年まで続けられた。 研究に参加した患者の大多数である5万人以上が、抗うつ薬による治療を受けた。その結果、うつ病の治療をすることで、糖尿病患者の死亡率を低下できることが示された。 reversible inhibitor of monoamine oxidase A (RIMA)では増えるらしい（日本では使っていないようであるが） https://dm-net.co.jp/calendar/2019/029298.php

  23. http://uwb01.bml.co.jp/kensa/search/detail/3802486

  24. 1Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland beckey.trinh@usb.ch. 2Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland. 3Department of Biomedicine, University Hospital Basel, Basel, Switzerland. 4Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. Diabetes Care. 2019 Jul 15. pii: dc190908. doi: 10.2337/dc19-0908.

  25. a case of a 53-year-old male patient with melanoma who was treated with combination immune checkpoint blockade (ICB) with ipilimumab and nivolumab. The patient had advanced disease with metastasis to the liver, lung, and lymph nodes. After two doses of ICB, the patient developed hypocalcemia as a result of an immune-mediated hypoparathyroidism that was treated with calcium and vitaminDsubstitution. In addition, the patient suffered from immune-related colitis that required treatment with corticosteroids and two doses of infliximab. Combination immunotherapy led to a metabolic complete remission of the melanoma. After tapering corticosteroids, the patient was continued on nivolumab for several weeks. No abnormalities of blood glucose were noted until then in an otherwise lean patient with a BMI of 19.6 kg/m2. When the patient developed a seronegative oligoarthritis affecting the right knee and both ankles, he was treated with local corticosteroid injections, but no systemic corticosteroids were used. ICB was stopped. Several days later, the patient was seen for progressive fatigue. Laboratory testing showed a mild hyponatremia and a random blood glucose of 22.3 mmol/L. HbA1c was 11.6% (103 mmol/mol), and C-peptide was 933 pmol/L.

  26. A mixed meal tolerance test (MMTT) revealed a mixed dysfunction, including impaired insulin secretion and reduced peripheral insulin sensitivity. Autoantibodies against islet cells were positive. Despite peripheral insulin resistance, positive autoantibodies and impaired insulin secretion led to the diagnosis of animmune-mediated diabetes mellitus (DM) similar to a type 1 DM with mixed features of b-cell dysfunction and peripheral insulin resistance. Because CRP levels were low throughout the observation period, systemic inflammation as the main cause of the hyperglycemia was also unlikely. Treatment with insulin injections was begun. Initially, a daily average of 17 units insulin was required. Because the patient also developed a more active oligoarthritis, we started a therapy with infliximab to block tumor necrosis factor-a (TNF-a). Treatment with infliximab resulted in a reversal of b -cell dysfunction and insulin resistance, and insulin therapy could be stopped. Restaging of the patient 2months after the last insulin injection and infliximab dose demonstrated an ongoing complete remission of his diabetes. Glucose:5mmol/L=90mg/dL Insulin:基準値2.2～12.4 μU/mL 1 μU/ml = 6 pmol/L = 1 mU/L C-peptide:基準値 0.8～2.5 ng/mL1 ng/mL = 3.003003 nmol/L = 3003.003 pmol/L http://www.endmemo.com/medical/unitconvert/C-peptide.php

  27. 0.6g/mL 8.3μU/mL 90mg/dL

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