superman 2010-6-9 10:20
長期使用Metformin治療與維他命B12不足有關
作者：Laurie Barclay, MD
出處：WebMD醫學新聞
May 24, 2010 — 根據發表於5月20日線上搶先版BMJ期刊的多中心隨機安慰劑控制試驗，在第2型糖尿病患中，長期使用metformin治療與維他命B12不足有關。
荷蘭阿姆斯特丹學院醫學中心的Jolien de Jager等人寫道，Metformin被視為糖尿病治療的基礎，也是第2型糖尿病患者最常被開方使用的第一線治療藥物，此外，它是與改善心血管發病率和死亡率(第2型糖尿病患者的主要死因)有關的少數降血糖藥物之一。不過，Metformin會引起維他命B12吸收不良，增加發生維他命B12不足的風險—這是一種有臨床重要性且可治療的狀況。
此試驗的目標是確認metformin對於發生維他命B12不足的影響，維他命B12不足的定義是濃度小於150 pmol/L，維他命B12低的定義是濃度150 - 220 pmol/L，另外也測量葉酸和同半胱胺酸的濃度。
在荷蘭的3個非大學醫院門診的病患中，使用胰島素治療的390名第2型糖尿病患者，接受850 mg的metformin或安慰劑、每天3次、為期4.3年。主要研究終點是，在4、17、30、43和52個月時，相較於開始時的維他命B12、葉酸、同半胱胺酸濃度變化百分比。
相較於安慰劑組，metformin組的維他命B12濃度平均減少19% (95%信心區間[CI]為-24%至-14%；P < .001)，葉酸濃度平均減少5% (95% CI，-10%至-0.4%；P = .033)，同半胱胺酸濃度平均增加5% (95% CI，-1%至11%；P = .091)。校正身體質量指數與抽菸情況之後，Metformin對於葉酸濃度並無顯著影響。
研究結束時，維他命B12不足的絕對風險方面，metformin組比安慰劑組高出7.2個百分點(95% CI，2.3 - 12.1；P = .004)，換算成需傷害之病患人數為每4.3年有13.8人(95% CI，43.5 - 8.3)。至於研究結束時的低維他命B12濃度的絕對風險，metformin組比安慰劑組高出11.2個百分點(95% CI，4.6 - 17.9；P = .001)，換算成需傷害之病患人數為每4.3年有8.9人(95% CI，21.7 - 5.6)。
研究結束時，維他命B12不足的病患中，平均同半胱胺酸濃度為23.7 μmol/L (95% CI，18.8 - 30.0 μmol/L)，低維他命B12濃度的病患則是18.1 μmol/L (95% CI，16.7 - 19.6 μmol/L；P = .003)，維他命B12濃度正常的病患則是14.9 μmol/L。
研究作者寫道，長期使用metformin治療增加了維他命B12不足的風險，導致同半胱胺酸濃度增加，維他命B12不足是可以預防的；因此，我們的發現認為，長期使用metformin治療時，應考慮定期測量維他命B12濃度。
研究限制包括，只有測量總維他命B12濃度，而沒有分別測量全反鈷胺素II(holotranscobalamin II)或甲基丙二酸(methylmalonic acid)，可能低估了metformin治療對於有臨床重要性之維他命B12不足的影響。
【編輯評論：飲食諮商有所幫助】
英國威爾斯Cardiff健康園區一線照護與公共衛生部Josep Vidal-Alaball和Christopher C. Butler在編輯評論中指出，建議探討在開始使用metformin治療時和追蹤期間進行飲食諮商是否有助於解決這個問題。
Vidal-Alaball醫師和Butler醫師寫道，如果沒效，就需要對服用metformin的病患進行維他命B12篩檢試驗，服用metformin的病患(不論有無同時使用胰島素)都應隨機進行系統性血清維他命B12篩檢或者例行性照護，將病患導向之結果與費用都納入效果考量，此外，藉由治療生化結果，我們冒著增加病患負擔與照護費用之風險，而非對病患重要的結果。
Altana、Lifescan、Merck Sante、Merck Sharp Dohme以及Novo Nordisk等藥廠提供資金支持此研究。研究作者們與編輯們皆宣告沒有相關財務關係。
BMJ.線上發表於2010年5月20日。
Long-Term Metformin Treatment Linked to Vitamin B12 Deficiency
By Laurie Barclay, MD
Medscape Medical News
May 24, 2010 — In type 2 diabetes, long-term metformin treatment is linked to vitamin B12 deficiency, according to the results of a multicenter, randomized, placebo-controlled trial reported Online First May 20 in the BMJ.
"Metformin is considered a cornerstone in the treatment of diabetes and is the most frequently prescribed first line therapy for individuals with type 2 diabetes," write Jolien de Jager, from the Academic Medical Center in Amsterdam, the Netherlands, and colleagues. "In addition, it is one of a few antihyperglycaemic agents associated with improvements in cardiovascular morbidity and mortality, which is a major cause of death in patients with type 2 diabetes....Metformin does, however, induce vitamin B-12 malabsorption, which may increase the risk of developing vitamin B-12 deficiency — a clinically important and treatable condition."
The goal of this trial was to determine the effects of metformin on the incidence of vitamin B12 deficiency, defined as vitamin B12 levels of less than 150 pmol/L and low levels of vitamin B12 (150 - 220 pmol/L), as well as on folate and homocysteine concentrations.
At the outpatient clinics of 3 nonacademic hospitals in the Netherlands, 390 patients with type 2 diabetes being treated with insulin received 850 mg of metformin or placebo 3 times daily for 4.3 years. The primary study endpoints were percentage change from baseline in vitamin B12, folate, and homocysteine concentrations at 4, 17, 30, 43, and 52 months.
The metformin group vs the placebo group had a mean decrease in vitamin B12 concentration of ?19% (95% confidence interval [CI], ?24% to ?14%; P < .001), a mean decrease in folate concentration of ?5% (95% CI, ?10% to ?0.4%; P = .033), and a mean increase in homocysteine concentration of 5% (95% CI, ?1% to 11%; P = .091). Metformin had no significant effect on folate concentrations, after adjustment for body mass index and smoking.
At the end of the study, the absolute risk for vitamin B12 deficiency was 7.2 percentage points higher with metformin vs placebo (95% CI, 2.3 - 12.1; P = .004), yielding a number needed to harm of 13.8 per 4.3 years (95% CI, 43.5 - 8.3). For low vitamin B12 concentrations at study end, the absolute risk was 11.2 percentage points higher with metformin vs placebo (95% CI, 4.6 - 17.9; P = .001), and number needed to harm was 8.9 per 4.3 years (95% CI, 21.7 - 5.6).
Among patients who had vitamin B12 deficiency at the end of the study, mean homocysteine level was 23.7 μmol/L (95% CI, 18.8 - 30.0 μmol/L) vs 18.1 μmol/L (95% CI, 16.7 - 19.6 μmol/L; P = .003) among patients who had low vitamin B12 concentration and 14.9 μmol/L among patients who had normal vitamin B12 concentration.
"Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations," the study authors write. "Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered."
Limitations of this study include measurement only of total vitamin B12 levels and not levels of holotranscobalamin II or methylmalonic acid, and possible underestimation of the impact of metformin treatment on the risk for clinically important vitamin B12 deficiency.
Editorial: Dietary Counseling May Help
In an accompanying editorial, Josep Vidal-Alaball and Christopher C. Butler, from the Department of Primary Care and Public Health in Heath Park, Cardiff, Wales, United Kingdom, recommend determining whether simple dietary counseling when metformin is started and at follow-up would solve the problem.
"If it does not, a trial of screening for vitamin B-12 deficiency in patients taking metformin would be needed," Drs. Vidal-Alaball and Butler write. "Patients taking metformin (not just those also treated with insulin) should be randomised to systematic serum vitamin B-12 screening or routine care, with patient oriented outcomes and costs included in the outcomes. Otherwise, we risk increasing the burden on patients and the costs of care by treating biochemical outcomes rather than outcomes that matter to patients."
Grants from Altana, Lifescan, Merck Sante, Merck Sharp Dohme, and Novo Nordisk supported this study. The study authors and editorialists have disclosed no relevant financial relationships.
BMJ. Published online May 20, 2010.