Interventions for latent autoimmune diabetes (LADA) in adults

 

Abstract

Background

Latent autoimmune diabetes in adults (LADA) is a slowly developing type 1 diabetes.

Objectives

To compare interventions used for LADA.

Search methods

Studies were obtained from searches of electronic databases, supplemented by handsearches, conference proceedings and consultation with experts. Date of last search was December 2010.

Selection criteria

Randomised controlled trials (RCT) and controlled clinical trials (CCT) evaluating interventions for LADA or type 2 diabetes with antibodies were included.

Data collection and analysis

Two authors independently extracted data and assessed risk of bias. Studies were summarised using meta-analysis or descriptive methods.

Main results

Searches identified 13,306 citations. Fifteen publications (ten studies) were included, involving 1019 participants who were followed between three months to 10 years (1060 randomised). All studies had a high risk of bias. Sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone at three months (one study, n = 15) and at 12 months (one study, n = 14) of treatment and follow-up. SU (with or without metformin) gave poorer metabolic control compared to insulin alone (mean difference in glycosylated haemoglobin A1c (HbA1c) from baseline to end of study, for insulin compared to oral therapy: -1.3% (95% confidence interval (CI) -2.4 to -0.1; P = 0.03, 160 participants, four studies, follow-up/duration of therapy: 12, 30, 36 and 60 months; however, heterogeneity was considerable). In addition, there was evidence that SU caused earlier insulin dependence (proportion requiring insulin at two years was 30% in the SU group compared to 5% in conventional care group (P < 0.001); patients classified as insulin dependent was 64% (SU group) and 12.5% (insulin group, P = 0.007). No intervention influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5)). In a five year follow-up of GAD65 (glutamic acid decarboxylase formulated with aluminium hydroxide), improvements in fasting and stimulated C-peptide levels (20 μg group) were maintained after five years. Short term (three months) follow-up in one study (n = 74) using Chinese remedies did not demonstrate a significant difference in improving fasting C-peptide levels compared to insulin alone (0.07 µg/L (95% CI -0.05 to 0.19). One study using vitamin D with insulin showed steady fasting C-peptide levels in the vitamin D group but declining fasting C-peptide levels (368 to 179 pmol/L, P = 0.006) in the insulin alone group at 12 months follow-up. Comparing studies was difficult as there was a great deal of heterogeneity in the studies and in their selection criteria. There was no information regarding health-related quality of life, complications of diabetes, cost or health service utilisation, mortality and limited evidence on adverse events (studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic episodes).

Authors' conclusions

Two studies show SU leading to earlier insulin dependence and a meta-analysis of four studies with considerable heterogeneity showed poorer metabolic control if SU is prescribed for patients with LADA compared to insulin. One study showed that vitamin D with insulin may protect pancreatic beta cells in LADA. Novel treatments such as GAD65 in certain doses (20 μg) have been suggested to maintain fasting and stimulated C-peptide levels. However, there is no significant evidence for or against other lines of treatment of LADA.

 

Plain language summary

Interventions for latent autoimmune diabetes (LADA) in adults

LADA is a condition that at diagnosis looks like type 2 diabetes (non-insulin requiring diabetes mellitus) but actually is a type 1 diabetes, where the patient will become insulin requiring. In the UK approximately 3.6% of people who look like they have type 2 diabetes actually have type 1 diabetes, while other studies suggest the prevalence is higher and treatment for these patients may need to be different from that used in type 2 diabetes.
We identified 15 publications (10 studies) looking at 1019 patients who were followed between three months to 10 years. We found many of the publications had poor quality of reporting and had small numbers of participants. However, there does seem to be evidence from this review that the drug sulphonylurea (like glibenclamide or glyburide, gliclazide) could make patients insulin dependent sooner and it does not control blood sugar as well as insulin. Therefore, this suggests that this drug should not be a first line treatment for patients with LADA. In addition, insulin combined with vitamin D, or Chinese herbs may maintain natural insulin production better than insulin alone. Similarly, glutamic acid decarboxylase (GAD65) may maintain natural insulin production. However, there was no conclusive evidence that any of the other remaining treatment methods were better than each other. Studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic attacks.

This review represents very early days of our understanding of the best way to treat LADA. It is limited by the poor reporting quality of the studies, small sample sizes, no clear single definition of LADA and many of the studies being carried out in different ethnic groups (China, Japan, Cuba, UK, Sweden) with different clinical care systems.
None of the publications reported on complications of diabetes, health-related quality of life, costs or health service utilisation. All but one of the publications reported there were no deaths.
In summary, this review demonstrates that insulin treatment may be preferable compared to sulphonylurea treatment but there is little evidence regarding other forms of treatment. Future studies are needed, should have a clear definition of LADA, investigate patient-important outcomes and use a common method of measuring stimulated C-peptide (a marker of natural insulin production reflecting improved beta-cell function of the pancreas).

 

摘要

背景

治療成人潛伏性自體免疫糖尿病(LADA)的介入措施

成人潛伏性自體免疫糖尿病(LADA)是一個緩慢發展的第1型糖尿病，一開始表現為非胰島素依賴型糖尿病而後進展成胰島素依賴性。然而，LADA的最佳的治療策略尚不清楚。

目標

比較用於成人潛伏性自體免疫糖尿病的介入措施。

搜尋策略

研究是從搜索電子資料庫(包括了MEDLINE，EMBASE)，輔以手工檢索，會議記錄和諮詢專家所獲得。

選擇標準

篩選是一式兩份，由兩個獨立的回顧者進行。評估LADA或帶有抗體之第2型糖尿病之干預的隨機對照試驗和控制型臨床試驗也被包括在內。

資料收集與分析

兩名回顧者獨立地摘錄資料和評估研究的品質。研究以描述的方式作總結。

主要結論

檢索確認了8067篇引文。包括8份出版刊物(有7項研究)，涉及735位參與者。所有的研究都有高偏差風險。沒有關於單獨使用metformin或glitazones的資料。rosiglitazone或磺醯尿素(SU)合併胰島素沒有比單用胰島素明顯地改善代謝控制。與單用胰島素(2個研究)比，單用SU得到較差的(1個研究，糖化血色素平均差2.8％(95％CI 0.9至4.7)或相當的代謝控制。有證據顯示，SU造成較早的胰島素依賴(胰島素治療在2年時：30％ (SU) 和5％(常規照護) (P <0.001);歸類為胰島素依賴型：64％(SU)和12.5％(胰島素組)(P = 0.007))。沒有任何干預影響到空腹C胜?，但胰島素維持受刺激的C胜?濃度優於SU(1個研究，平均差7.7ng/ml (95％ CI 2.9至12.5))，且胰島素合併rosiglitazone在維持受刺激的C胜?濃度上優於單用胰島素(1個研究)。一項前驅性研究顯示，與安慰劑相比，皮下投予谷氨酸脫羧?(GAD)，一種主要的自體免疫性糖尿病抗原，在6個月時可得到更好的代謝控制。在任何的出版品中，沒有與生活品資，死亡率，併發症或費用有關的資訊。診斷的時間從於診斷時徵募到罹病已9年時徵募不等，且LADA患者的選擇標準也有很大的差異，因此很難從這些研究中得到概括發現。

作者結論

很少有關於這一主題的研究且現有的研究具有高偏差風險。然而，似乎存在一個跡象，SU不應做為抗體陽性之第2型糖尿病的第一線治療。沒有明顯的證據支持或反對其他線藥物在LADA上的治療。

翻譯人

本摘要由慈濟醫院李哲全翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

治療成人潛伏性自體免疫糖尿病(LADA)的最佳方法仍是未知。LADA是診斷時看起來像第2型糖尿病(非胰島素需求)，但實際上是第1型糖尿病的一種狀況，患者終將成為胰島素需求。大約10％看起來像是第2型糖尿病的人，實際上是第1型糖尿病，而這些患者可能需要使用不同於第2型糖尿病的治療。本回顧確認出8份出版刊物，檢視了735位病患，追蹤6個月至10年。我們發現許多出版刊物的報告品質不佳，且參與者的數目小。然而，從本回顧，似乎有證據顯示磺醯尿素類藥物可能使患者較快變成胰島素依賴，且不能提供比其他可能的治療方法更好的血糖控制。因此，這暗示，這種藥物不應成為LADA病人的第一線治療。但是，沒有確鑿的證據證明，任何其他的治療方法明顯優於彼此。本回顧代表我們對治療LADA之最佳方法的最早期暸解。它受限於不佳的研究報告品質，小樣本量，沒有明確的LADA單一定義，及許多研究是在有不同臨床照護系統之不同民族(中國，日本，古巴，英國，瑞典)中所完成。 沒有任一出版刊物報告糖尿病的併發症，生活品質，成本或健康服務利用。幾乎只有一份出版刊物報告無死亡事件。在追蹤患者達10年的研究中，我們預期有死亡事件，但沒有這樣的報告。總之，本回顧呈現幾乎沒有治療LADA之最佳方法的證據，未來進一步的研究是需要的。未來的研究應該有一個明確的LADA定義，及在報告調查結果上依循設定的標準。