高血壓患者的無聲警訊：NT-proBNP 揭露隱性心臟功能異常

Abstract 摘要

Glycated haemoglobin (HbA1c) is currently the gold standard outcome measure for type 2 diabetes trials. Time in range is a continuous glucose monitoring (CGM) metric defined as the proportion of time in euglycemia (3.9–10.0 mmol/L) and may be valuable not only in type 1 diabetes clinical trials but also as an endpoint in type 2 diabetes trials. This narrative review aimed to assess the relative merits of time in range versus HbA1c as outcome measures for type 2 diabetes studies. It reviews the strengths and limitations of time in range as an outcome measure and evaluates studies in type 2 diabetes that have used time in range as a primary or secondary outcome measure. A literature search was conducted on PubMed and MEDLINE databases using key terms “time in range” AND “diabetes” OR “type 2 diabetes mellitus”. Further evidence was obtained from relevant references of retrieved articles. Literature search identified 247 papers, of which 110 were included in this review. These included a broad range of articles, including 45 randomized trials using time in range as an outcome measure in patients with type 2 diabetes, as well as papers validating time in range. Time in range provides valuable and clinically relevant information and should be used as an important endpoint in type 2 diabetes in clinical trial settings, in conjunction with HbA1c.

糖化血色素（HbA1c）目前是 2 型糖尿病試驗的黃金標準結果指標。血糖範圍時間（Time in range, TIR）是一種連續血糖監測（CGM）指標，定義為血糖處於正常血糖範圍（3.9–10.0 mmol/L）的時間比例，它不僅在 1 型糖尿病臨床試驗中有價值，也可作為 2 型糖尿病試驗的終點指標。本篇敘述性回顧旨在評估 TIR 與 HbA1c 作為 2 型糖尿病研究結果指標的相對優勢。本文回顧了 TIR 作為結果指標的優點與限制，並評估了在 2 型糖尿病研究中使用 TIR 作為主要或次要結果指標的相關研究。我們在 PubMed 和 MEDLINE 資料庫中，使用關鍵字「time in range」和「diabetes」或「type 2 diabetes mellitus」進行文獻檢索。此外，也從檢索到的文章的相關參考文獻中獲取進一步的證據。文獻檢索共識別出 247 篇論文，其中 110 篇被納入本次回顧。這些論文涵蓋了廣泛的文章類型，包括 45 篇使用 TIR 作為 2 型糖尿病患者結果指標的隨機試驗，以及驗證 TIR 的相關論文。TIR 提供了有價值且臨床相關的資訊，應在臨床試驗中與 HbA1c 結合使用，作為 2 型糖尿病的重要終點指標。

Keywords: consensus recommendations, continuous glucose monitoring, diabetes mellitus, HbA1c, time in range(s), type 2
關鍵字：共識建議、連續血糖監測、糖尿病、HbA1c、血糖範圍時間、2 型

1. INTRODUCTION 1. 前言

Glycated haemoglobin (HbA1c) has long been considered the gold standard for assessing long‐term glycaemia in people with type 2 diabetes. Continuous glucose monitoring (CGM) devices have become widely used, not just for people living with type 1 diabetes but also for those with type 2 diabetes. ¹ CGM measures glucose levels in the interstitial fluid every 1–15 min, and an average glucose is recorded every 5–15 min for 24 h a day continuously. CGM enables better visualization and understanding of glucose levels by people with diabetes. Time in range (TIR) is a CGM metric which, by consensus, represents the percentage of time that glucose readings are within the desired range of 3.9–10.0 mmol/L (70–180 mg/dL). This metric has been increasingly used as an outcome measure to assess diabetes management both in clinical practice and clinical trials, especially in those trials involving people with type 1 diabetes. ²

糖化血色素（HbA1c）長期以來被認為是評估 2 型糖尿病患者長期血糖控制的黃金標準。連續血糖監測（CGM）裝置已廣泛使用，不僅用於 1 型糖尿病患者，也用於 2 型糖尿病患者。 ¹ CGM 每 1 至 15 分鐘測量一次組織間液的葡萄糖水平，並持續記錄 24 小時的平均血糖值，每 5 至 15 分鐘記錄一次。CGM 讓糖尿病患者能更好地視覺化和理解其血糖水平。血糖範圍時間（Time in range, TIR）是一項 CGM 指標，根據共識，代表血糖讀數落在期望範圍 3.9–10.0 mmol/L（70–180 mg/dL）內的時間百分比。這項指標越來越多地被用作評估糖尿病管理結果的指標，無論是在臨床實務或臨床試驗中，尤其是在涉及 1 型糖尿病患者的試驗中。 ²

The use of CGM in type 2 diabetes research is increasing. It is a useful tool to not only improve glycaemic management but also to more accurately assess the impact of interventions on diabetes management. Batelino et al. ³ have made consensus recommendations on the use of CGM for clinical trials to assess the impact of an intervention; therefore, an increasing number of trials are using TIR as an outcome measure.

連續血糖監測（CGM）在第二型糖尿病研究中的使用日益增加。它不僅是改善血糖管理的有用工具，也能更準確地評估介入措施對糖尿病管理的影響。Batelino 等人 ³ 已針對在臨床試驗中使用 CGM 評估介入措施影響提出共識性建議；因此，越來越多的試驗將「目標範圍內時間」（TIR）作為結果指標。

HbA1c has been the gold standard assessment of diabetes management for 29 years, since the publication of the Diabetes Control and Complications Trial (DCCT) which showed that an elevated HbA1c was associated with an increased risk of development and progression of microvascular complications. ⁴ HbA1c is measured based on the non‐enzymatic glycation of haemoglobin, from which blood glucose levels over the normal ~120‐day life span of the red blood cell can be inferred.

自糖尿病控制與併發症試驗（DCCT）發表以來，糖化血色素（HbA1c）已成為糖尿病管理的黃金標準評估指標長達 29 年，該試驗顯示糖化血色素升高與微血管病變的發生及進展風險增加有關。 ⁴ 糖化血色素的測量是基於血紅素的非酵素性醣化作用，可據此推斷紅血球約 120 天壽命期間的血糖水平。

HbA1c is an indirect measure of glycaemic exposure and may not accurately reflect glycaemia in people with haemoglobinopathies, anaemia, kidney failure and even some ethnic groups, due to differences in the propensity of haemoglobin to glycosylation (Table S1 appendix). Some studies have shown HbA1c measurements are higher in US African Americans and Hispanic populations than in Caucasians. ⁵ These differences can make HbA1c a less reliable marker of glycaemia in certain populations. Therefore, management decisions in those with type 2 diabetes may be better served by CGM measures, including TIR.

糖化血色素是血糖暴露的間接測量指標，由於血紅素醣化傾向的差異（附錄表 S1 ），它可能無法準確反映患有血紅素病變、貧血、腎衰竭甚至某些族裔群體的血糖情況。一些研究顯示，美國非裔和西班牙裔族群的糖化血色素測量值高於白種人。 ⁵ 這些差異可能使糖化血色素成為某些族群血糖較不可靠的標記。因此，對於第二型糖尿病患者的治療決策，使用包括 TIR 在內的 CGM 測量可能更有助益。

Time in range (TIR) provides insight into short‐term glycaemic management in the clinical setting by providing real‐time feedback on glucose patterns. In research settings, TIR can be a valuable marker of the effectiveness of the trial intervention. There are other CGM metrics available, which will be discussed briefly later in this review; however, TIR is the most validated one so far. In this narrative review, we explore the strengths and limitations of TIR as an outcome measure with a review of trials in type 2 diabetes that have used TIR as either a primary or secondary outcome. We propose that TIR should be used routinely as an important outcome measure in type 2 diabetes trials in conjunction with HbA1c. Diabetes in pregnancy is beyond the scope of this review.

目標範圍內時間（TIR）透過提供血糖模式的即時回饋，深入了解臨床環境中的短期血糖管理。在研究方面，TIR 可以作為試驗介入措施有效性的寶貴指標。還有其他 CGM 指標可供使用，將在本篇回顧中稍後簡要討論；然而，TIR 是迄今為止經過最多驗證的指標。在本篇敘述性回顧中，我們將探討 TIR 作為結果指標的優缺點，並回顧在第二型糖尿病試驗中將 TIR 作為主要或次要結果的研究。我們建議在第二型糖尿病試驗中，應將 TIR 與糖化血色素結合，作為重要的常規結果指標。懷孕期間的糖尿病不在本回顧的討論範圍內。

2. METHODS 2. 方法

We conducted a literature search on the PubMed and MEDLINE databases using medical subject heading (MeSH) terms “time in range” AND “diabetes” OR “type 2 diabetes mellitus” OR “diabetes mellitus” OR “glycemic control” OR “glycated haemoglobin” OR “diabetes treatment” OR “glucose‐lowering drugs” OR “diabetes complications” OR “microvascular complications” OR “macrovascular complications”. Retrieved articles were filtered to remove duplicates and irrelevant results. The reference lists of the selected articles were also searched for any relevant papers. Relevant papers on TIR, HbA1c and CGM in type 2 diabetes published since year 2000 were included. The search was limited to humans, and the English language.

我們使用醫學主題詞（MeSH）「time in range」 AND 「diabetes」 OR 「type 2 diabetes mellitus」 OR 「diabetes mellitus」 OR 「glycemic control」 OR 「glycated haemoglobin」 OR 「diabetes treatment」 OR 「glucose‐lowering drugs」 OR 「diabetes complications」 OR 「microvascular complications」 OR 「macrovascular complications」在 PubMed 和 MEDLINE 資料庫進行文獻檢索。檢索到的文章經過篩選，以移除重複和不相關的結果。同時也檢索了所選文章的參考文獻列表，以尋找任何相關論文。我們納入了自 2000 年以來發表於第二型糖尿病領域，關於 TIR、HbA1c 和 CGM 的相關論文。檢索範圍限於人類和英文文獻。

3. RESULTS 3. 結果

A total of 1260 potentially relevant articles were identified. After screening for relevance, 110 articles were included in this review (Figure 1). A Medline search using the MeSH terms “time in range” AND “diabetes mellitus, type 2” yielded 247 results, including 45 randomized controlled trials involving individuals with Type 2 diabetes, where TIR was considered either a primary or secondary outcome (Table 1). Of these, 11 studies featured CGM as the intervention. Specifically, 21 studies used TIR as a primary outcome, 19 as a secondary outcome and 5 as a co‐primary outcome. Studies that used TIR as the primary outcome, without including HbA1c as an outcome, had durations ranging from 13 days to 3 months, with a median duration of 51.5 days. All studies that included HbA1c as a primary or secondary outcome were greater than 3 months duration, with a median duration of 58 weeks duration. The trials were conducted across a diverse set of countries, including the United States, United Kingdom, Japan, Korea, China, Australia, Canada, Singapore and several European nations. The most commonly used CGM devices were the FreeStyle Libre Pro by Abbott, employed in 13 studies, Medtronic products in 10 studies, followed by the Dexcom G6 in 8 studies, and the Dexcom G4 in 2 studies. Additionally, 3 studies derived TIR from self‐monitoring of blood glucose through fingerpricking.

總共識別出 1260 篇潛在相關的文章。經過相關性篩選後，本篇回顧納入了 110 篇文章（圖 1 ）。使用 MeSH 術語「time in range」和「diabetes mellitus, type 2」進行 Medline 搜尋，共得到 247 個結果，其中包括 45 項針對第二型糖尿病患者的隨機對照試驗，其中 TIR 被列為主要或次要結果（表 1 ）。其中，有 11 項研究以連續血糖監測 (CGM) 作為介入措施。具體而言，有 21 項研究將 TIR 作為主要結果，19 項作為次要結果，5 項作為共同主要結果。將 TIR 作為主要結果且未包含 HbA1c 作為結果的研究，其持續時間從 13 天到 3 個月不等，中位持續時間為 51.5 天。所有將 HbA1c 作為主要或次要結果的研究，其持續時間均超過 3 個月，中位持續時間為 58 週。這些試驗在多個國家進行，包括美國、英國、日本、韓國、中國、澳洲、加拿大、新加坡以及數個歐洲國家。最常使用的 CGM 裝置是 Abbott 的 FreeStyle Libre Pro，用於 13 項研究；Medtronic 的產品用於 10 項研究；接著是 Dexcom G6，用於 8 項研究；Dexcom G4 則用於 2 項研究。此外，有 3 項研究是透過指尖採血自我監測血糖來計算 TIR。

FIGURE 1. 圖 1. TABLE 1. 表 1. Studies involving time in range as an outcome measure in people with type 2 diabetes. 涉及時間範圍作為第二型糖尿病患者結果指標的研究。

Abbreviations: CI, confidence interval; dTIR, derived time in range; EOT, end of treatment; FGM, flash glucose monitoring; SMBG, self‐monitored blood glucose; T1D, type 1 diabetes; T2D, type 2 diabetes.

縮寫：CI，信賴區間；dTIR，衍生時間範圍；EOT，治療結束；FGM，瞬時葡萄糖監測；SMBG，自我監測血糖；T1D，第一型糖尿病；T2D，第二型糖尿病。

4. DISCUSSION 4. 討論

The International Consensus on Time in Range (ICTR) defines targets for TIR, time above range (TAR) and time below range (TBR) for people with type 1 and type 2 diabetes. ⁵¹ They recommend assessing all the metrics together as ‘TIR’ in clinical and research settings as it is more illustrative overall. They recommend >70% of time spent within target ranges (around 16 h 48 min per day) for both type 1 and type 2 diabetes. ⁵² , ⁵³ TBR is split into two levels: Level 1 (3.0–3.9 mmol/L, 54–69 mg/dL) signals risk of hypoglycaemia, and Level 2 (<3.0 mmol/L, <54 mg/dL) is clinically significant, requiring immediate attention, with a target of <1% of the day. TAR is also split into two levels: Level 1 (>10 mmol/L, >180 mg/dL) and Level 2 (>13.9 mmol/L, >250 mg/dL).

國際時間範圍共識（ICTR）為第一型及第二型糖尿病患者定義了時間範圍（TIR）、高於範圍時間（TAR）及低於範圍時間（TBR）的目標。 ⁵¹ 他們建議在臨床和研究環境中將所有指標綜合評估為「TIR」，因為這能更全面地說明情況。他們建議第一型及第二型糖尿病患者有超過 70%的時間落在目標範圍內（約每天 16 小時 48 分鐘）。 ⁵² , ⁵³ TBR 分為兩個等級：等級 1（3.0–3.9 mmol/L，54–69 mg/dL）表示低血糖風險，等級 2（<3.0 mmol/L，<54 mg/dL）則具有臨床意義，需要立即關注，目標是每天少於 1%。TAR 也分為兩個等級：等級 1（>10 mmol/L，>180 mg/dL）和等級 2（>13.9 mmol/L，>250 mg/dL）。

TIR targets for specific subgroups, such as the elderly or other high‐risk individuals, have also been defined by the ICTR. A TIR target of >50% per day (12 h) for individuals over 60 years or those at high risk is recommended. ³ However, this target is based on consensus opinion considering the higher rates of hypoglycaemia and hypoglycaemia unawareness in older adults and is not well validated. ⁵⁴ A 2021 review involving 15 expert endocrinologists worldwide proposed individualized TIR targets for various subgroups ⁵⁵ (Figure 2). They endorsed the ICTR recommendation of >70% TIR at 3.9–10 mmol/L for individuals with type 1 and type 2 diabetes; however, for highly motivated, newly diagnosed patients without comorbidities, a stricter target of >80% TIR at 3.9–8.9 mmol/L may be considered.

針對特定族群，例如老年人或其他高風險族群，國際共識目標範圍（International Consensus on Time in Range, ICTR）也已定義了時間範圍（Time in Range, TIR）目標。建議 60 歲以上或高風險族群的每日 TIR 目標為>50%（12 小時）。 ³ 然而，此目標是基於共識意見，考量到老年人低血糖和低血糖無感知的發生率較高，且尚未得到充分驗證。 ⁵⁴ 2021 年一項涵蓋全球 15 位內分泌學專家的回顧性研究，為不同族群提出了個別化的 TIR 目標 ⁵⁵ （圖 2 ）。他們贊同 ICTR 建議第一型和第二型糖尿病患者在 3.9–10 mmol/L 的 TIR 目標為>70%；然而，對於積極性高、新診斷且無共病的患者，可以考慮在 3.9–8.9 mmol/L 的 TIR 目標為>80%。

FIGURE 2. 圖 2.

For adolescents with type 1 diabetes, the target was >80% TIR at 3.9–10 mmol/L, due to the propensity for greater glycaemic variability. Although difficult to achieve, dedicated education and support on carbohydrate counting, meal planning, exercise management and use of insulin pumps may help to achieve this. Additionally, for those with macrovascular complications, a more relaxed target (>70% TIR at 4.4–10 mmol/L) was recommended to mitigate the heightened risk with hypoglycemia. ⁵⁶ An even looser target (>70% TIR at 5.0–10 mmol/L) was suggested for patients with renal or hepatic disease. Individualized TIR targets are crucial, even in clinical trials, to minimize hypoglycaemia. A more streamlined consensus on subgroup‐specific targets by the ICTR would be beneficial.

對於第一型糖尿病的青少年，由於血糖變異性較大的傾向，目標為 3.9–10 mmol/L 的 TIR>80%。儘管難以達成，但透過專門的教育和支持，包括碳水化合物計算、飲食計畫、運動管理和胰島素幫浦的使用，可能有助於達成此目標。此外，對於有巨血管併發症的患者，建議放寬目標（4.4–10 mmol/L 的 TIR>70%），以降低低血糖的風險。 ⁵⁶ 對於患有腎臟或肝臟疾病的患者，建議的目標更為寬鬆（5.0–10 mmol/L 的 TIR>70%）。即使在臨床試驗中，個別化的 TIR 目標對於盡量減少低血糖也至關重要。由 ICTR 制定更精簡的族群特定目標共識將是有益的。

A correlation analysis conducted by Montaser et al. on 75,563 CGM profiles from studies involving both type 1 and type 2 diabetes identified two key clusters of CGM metrics: exposure to hyperglycaemia and risk of hypoglycemia. ⁵⁷ Together, these clusters account for 90% of the variance in CGM data. Hyperglycaemia is associated with TIR and the Glycemia Management Index (GMI), while hypoglycaemia correlates with TBR and the Coefficient of Variation (CV).

Montaser 等人對來自第一型和第二型糖尿病研究的 75,563 個 CGM 數據進行相關性分析，結果發現了兩個主要的 CGM 指標群集：高血糖暴露和低血糖風險。 ⁵⁷ 這兩個群集共同解釋了 CGM 數據 90% 的變異性。高血糖與 TIR 和血糖管理指數 (GMI) 相關，而低血糖則與 TBR 和變異係數 (CV) 相關。

GMI, previously known as the estimated HbA1c, is calculated from mean glucose levels using formulas validated in multiple studies. ⁵⁸ , ⁵⁹ CV%, which reflects glycaemic variability (GV), is calculated by dividing the standard deviation (SD) of sensor glucose (SG) values by the mean SG value over the same observation period x100, and a threshold of 36% has been shown to differentiate between stable and unstable glycemia. ⁶⁰ CV has been shown to be relatively sensitive and predictive of hypoglycaemia. ⁶⁰ , ⁶¹ The strengths and limitations of these measures are discussed later in this review. While the primary focus in this manuscript is on T2D, the rationale for emphasizing TIR has similar implications for T1D, given the comparable TIR targets and associated diabetes complication outcomes.

GMI，先前稱為估計 HbA1c，是根據平均血糖值使用多項研究驗證過的公式計算而來。 ⁵⁸ 、 ⁵⁹ CV% 反映了血糖變異性 (GV)，計算方式是將感測器血糖 (SG) 值的標準差 (SD) 除以同一觀察期間的平均 SG 值再乘以 100，而 36% 的閾值已被證明可以區分穩定和不穩定的血糖。 ⁶⁰ CV 已被證明相對敏感且能預測低血糖。 ⁶⁰ 、 ⁶¹ 這些指標的優缺點將在本篇回顧中進一步討論。雖然本文主要關注 T2D，但由於 TIR 目標和相關的糖尿病併發症結果相似，強調 TIR 的理由對 T1D 也有類似的意義。

In comparison to HbA1c, TIR is not affected by ethnicity, hemoglobinopathies or anaemia, making it a more reliable outcome measure of glycaemia in populations that often get excluded in studies using HbA1c as a primary outcome measure. Some trials in people with Type 2 diabetes have shown discrepancies in the significance of outcomes between HbA1c and TIR, as outlined below ¹⁹ , ⁴⁸ and shown TIR can be a valuable marker of the effectiveness of a trial, thus justifying the need for both outcome measures even further. Furthermore, consensus recommendations have been made on the optimal duration of CGM wear being 14 consecutive days with at least 70% wear for accurate interpretation of CGM metrics; however, this has not been well validated. ³ This measure of CGM accuracy was based on a study involving 257 people with type 1 diabetes who wore a CGM over 3 months that found that the incremental sampling of CGM data correlation to the full 3 months of CGM data improved with the number of days of data collected; however, there was a plateau at about 14 days with an R ² value of 0.84–0.86 for metrics including TIR, mean blood glucose and level 1 hyperglycaemia. ⁶² A subsequent study by Xing et al. provided similar findings. ⁶³ The aforementioned determinants defining a minimum valid CGM dataset have been used in clinical trials. ⁶⁴ However, a recent analysis of people with type 2 diabetes who were not using insulin found that a CGM wear duration of 7–10 days might be sufficient to accurately estimate TIR. ⁶⁵ They utilized CGM data from a randomized trial to compute TIR by sequentially adding daily CGM data until the cumulative TIR values for the glucose ranges of 3.9–7.8 mmol/L (70–140 mg/dL) and 3.9‐10 mmol/L (70–180 mg/dL) stabilized to ±2% of the final values. They found that ranges of 3.9‐10 mmol/L stabilized within 7 ± 3 days and ranges 70–140 mg/dL stabilized within 10 ± 3 days. ⁶⁵ The duration of wear may be even lower in type 2 diabetes and is a further advantage of TIR use in clinical trials to obtain results in a shorter timeframe. ⁶³ , ⁶⁵ Recent studies have shown significant improvements in the accuracy of CGM systems. Newer CGM models demonstrate enhanced performance compared to previous generations, with reduced mean absolute relative difference (MARD) and improved reliability. ⁶⁶ A novel subcutaneous glucose sensor exhibited consistent accuracy over 10 days of wear, with an overall MARD of 9.6% and minimal risk associated with glucose discrepancies. ⁶⁷ Advanced calibration algorithms have also contributed to accuracy improvements.

與糖化血色素（HbA1c）相比，時間在範圍內（TIR）不受種族、血紅蛋白病變或貧血的影響，使其成為血糖控制更可靠的結果指標，適用於那些在使用 HbA1c 作為主要結果指標的研究中經常被排除的族群。一些針對第二型糖尿病患者的試驗顯示，HbA1c 和 TIR 在結果顯著性上存在差異，如下文所述 ¹⁹ 、 ⁴⁸ ，並顯示 TIR 可以作為評估試驗有效性的有價值指標，進一步證明了同時使用這兩種結果指標的必要性。此外，已達成共識建議連續配戴連續血糖監測儀（CGM）至少 14 天，且配戴率至少達 70%，以準確解讀 CGM 指標；然而，這尚未得到充分驗證。 ³ 此 CGM 準確性測量是基於一項涉及 257 名第一型糖尿病患者的研究，他們在 3 個月內配戴 CGM，結果發現 CGM 數據的增量採樣與 3 個月完整 CGM 數據的相關性隨著收集數據天數的增加而提高；然而，在大約 14 天時出現了平台期，包括 TIR、平均血糖和第一級高血糖等指標的 R ² 值為 0.84–0.86。 ⁶² Xing 等人後續的研究提供了類似的發現。 ⁶³ 上述定義最低有效 CGM 數據集的決定因素已用於臨床試驗。 ⁶⁴ 然而，最近一項針對未服用胰島素的第二型糖尿病患者的分析發現，配戴 CGM 7–10 天可能足以準確估計 TIR。 ⁶⁵ 他們利用隨機試驗的 CGM 數據計算 TIR，方法是依序添加每日 CGM 數據，直到 3.9–7.8 mmol/L（70–140 mg/dL）和 3.9–10 mmol/L（70–180 mg/dL）血糖範圍的累積 TIR 值穩定在±2%的最終值。他們發現 3.9–10 mmol/L 的範圍在 7 ± 3 天內穩定，而 70–140 mg/dL 的範圍在 10 ± 3 天內穩定。 ⁶⁵ 第二型糖尿病患者的配戴時間可能更短，這也是 TIR 在臨床試驗中用於在更短時間內獲得結果的另一項優勢。 ⁶³ 、 ⁶⁵ 近期研究顯示 CGM 系統的準確性有顯著進步。新型 CGM 型號與前幾代相比，表現有所增強，平均絕對相對差異（MARD）降低，可靠性提高。 ⁶⁶ 一種新型皮下葡萄糖感測器在配戴 10 天後表現出一致的準確性，總體 MARD 為 9.6%，且與葡萄糖差異相關的風險極小。 ⁶⁷ 先進的校準演算法也對準確性提升做出了貢獻。

The following are 3 major supportive factors for TIR as an outcome measure for type 2 diabetes trials:
以下是支持 TIR 作為第二型糖尿病試驗結果指標的三個主要因素：

4.2.1. Correlation of TIR and HbA1c
4.2.1. TIR 與 HbA1c 的相關性

The use of TIR has been validated in several studies as it correlates well with HbA1c (Table 2). Beck et al. performed a cross‐sectional longitudinal analysis of datasets from four clinical trials that assessed the effectiveness of CGM in 545 participants with type 1 diabetes. All participants had a HbA1c measured at baseline and 6 months. They found that a TIR of 70% reflected an average HbA1c of 7% (53 mmol/mol) with a moderate correlation (r = −0.67) using Spearman partial correlation analysis. ⁷⁰ A 10% increase in TIR correlated with a 0.5% reduction in HbA1c. Importantly, they demonstrated that a given TIR corresponded to a wide range of possible HbA1c levels, further highlighting the limitations of HbA1c and the need for TIR to be incorporated into standard practice as a direct measure of glycaemia. In comparison, a correlation analysis from 18 randomized controlled trials that reported paired HbA1c and %TIR metrics in people with type 1 and type 2 diabetes (n = 1137) found a strong correlation (r = −0.84) between HbA1c and TIR using linear regression analysis and Pearson’s correlation coefficient. ⁷¹ The authors reported that every absolute 10% change in TIR was associated with a 0.8% (9 mmol/mol) change in HbA1C. The differences in these values between both studies were attributed to the differences in the number of studies analysed, the population characteristics and methods of blood glucose measurements. Beck et al. ⁷⁰ analysed 4 randomized trials using CGM in people with type 1 diabetes, whereas Vigersky et al ⁷¹ analysed 18 randomized trials with data over a 10‐year time period with CGM and self‐monitoring blood glucose in both type 1 and type 2 diabetes. It could be argued that Vigersky et al ⁷¹ have a more robust dataset representative of a wider population of people with diabetes. However, the majority of the population in both studies was Caucasian, and since the relationship of mean blood glucose to HbA1c differs by ethnicity, it may not apply to the non‐Caucasian population. Neither study specified whether people with kidney disease were included, which could lead to falsely lower HbA1c levels. ⁷² Additional prospective studies are required in this area. These two correlation analyses were carried out in a population with Type 1 diabetes.

時間範圍（TIR）的使用已在多項研究中得到驗證，因為它與糖化血色素（HbA1c）有良好的相關性（表 2 ）。Beck 等人對來自四項臨床試驗的數據集進行了橫斷面縱向分析，評估了連續血糖監測（CGM）在 545 名第一型糖尿病患者中的有效性。所有參與者在基線和 6 個月時都測量了 HbA1c。他們發現 70% 的 TIR 反映了平均 7%（53 mmol/mol）的 HbA1c，使用 Spearman 偏相關分析顯示中度相關性（r = −0.67）。 ⁷⁰ TIR 增加 10% 與 HbA1c 降低 0.5% 相關。重要的是，他們證明了給定的 TIR 對應於廣泛的可能 HbA1c 水平，這進一步突顯了 HbA1c 的局限性，以及將 TIR 作為血糖直接測量指標納入標準實踐的必要性。相比之下，一項對 18 項隨機對照試驗的相關性分析發現，在第一型和第二型糖尿病患者（n = 1137）中，HbA1c 和 TIR 百分比（%TIR）指標之間存在強烈相關性（r = −0.84），使用線性迴歸分析和 Pearson 相關係數。 ⁷¹ 研究人員報告稱，TIR 每絕對變化 10%，HbA1C 就會變化 0.8%（9 mmol/mol）。這兩項研究之間這些數值的差異歸因於分析研究數量、人群特徵和血糖測量方法的差異。Beck 等人 ⁷⁰ 分析了 4 項使用 CGM 的第一型糖尿病患者隨機試驗，而 Vigersky 等人 ⁷¹ 分析了 18 項隨機試驗，其中包含第一型和第二型糖尿病患者使用 CGM 和自我監測血糖的 10 年時間數據。可以說，Vigersky 等人 ⁷¹ 的數據集更為穩健，更能代表更廣泛的糖尿病患者群體。然而，兩項研究中的大多數人群為高加索人，由於平均血糖與 HbA1c 的關係因種族而異，因此可能不適用於非高加索人群。沒有一項研究明確指出是否包含腎臟疾病患者，這可能導致 HbA1c 水平被錯誤地降低。 ⁷² 此領域需要額外的預測性研究。這兩項相關性分析是在第一型糖尿病患者群體中進行的。

TABLE 2. 表 2. Correlation between time in range (3.9–10 mmol/L, 70–180 mg/dL) and HbA1c in 2 meta‐analysis of randomized controlled trials. 時間在範圍內（3.9–10 mmol/L，70–180 mg/dL）與糖化血色素（HbA1c）在隨機對照試驗的兩項統合分析中的相關性。

Authors  作者	Study size (n), study type 研究規模（n）、研究類型	Population  研究對象	Study Aim(s)  研究目的	Findings  研究結果	Correlation coefficient (r) between time in range and HbA1c 時間範圍與糖化血色素（HbA1c）的相關係數（r）
Beck et al.  Beck 等人	545, Retrospective analysis of data from 4 RCTs 545、來自 4 項隨機對照試驗的數據回溯性分析	Type 1 diabetes = all studies 第一型糖尿病 = 所有研究	To better understand the metrics of time in range and hyperglycaemia and their relationship to HbA1c 為了更深入了解時間範圍和高血糖的指標及其與糖化血色素的關係	TIR of 70% corresponded with A1C of 7%, TIR of 50% corresponded with A1c of 8% 時間範圍 70%對應糖化血色素 7%，時間範圍 50%對應糖化血色素 8%	r = −0.67
				Every 10% increase in TIR = 0.5% (5.5 mmol/mol) A1C reduction 68 , 69 每增加 10% 的 TIR = A1C 降低 0.5% （5.5 mmol/mol） 68 ， 69
Vigersky et al.  Vigersky 等人	1440, Retrospective analysis of data from 18 RCTs 1440，來自 18 項隨機對照試驗的回顧性資料分析	Type 1 diabetes = 15 studies 第一型糖尿病 = 15 項研究	To understand the relationship between time in range and HbA1c 了解時間範圍與糖化血色素之間的關係	TIR of 70% corresponded with A1C of 6.7% 70%的時間範圍相當於 6.7%的糖化血色素	r = −0.84
		Type 2 diabetes = 4 studies 第二型糖尿病 = 4 項研究		Every 10% increase in TIR = 0.8% (8.7 mmol/mol) A1C reduction TIR 每增加 10% = A1C 降低 0.8% (8.7 mmol/mol)

4.2.2. Association between TIR and diabetes complications
4.2.2. 時間範圍與糖尿病併發症的關聯

Reduced TIR is associated with increased risk of microvascular complications. A retrospective analysis by Beck et al. involving 1440 participants from the DCCT estimated TIR based on seven daily blood glucose measurements every three months for a year. ⁷³ Participants with a TIR <30% had a significantly higher incidence of retinopathy compared to those with TIR ≥50% (38% vs. 8%). Each 10% reduction in TIR was associated with a 64% increased risk of retinopathy. Additionally, 27% of those with a TIR <10% developed microalbuminuria, compared to 3% of those with a TIR ≥70%. While this study highlights an association between TIR and microvascular complications, the data were based on limited seven‐point finger‐prick measurements, which may not fully capture long‐term TIR trends.
較低的 TIR 與微血管併發症風險增加有關。Beck 等人的一項回顧性分析，納入了 DCCT 的 1440 名參與者，估計 TIR 是根據一年內每季七次的每日血糖測量值。TIR <30%的參與者與 TIR ≥50%的參與者相比，視網膜病變的發生率顯著較高（38% vs. 8%）。TIR 每降低 10%，視網膜病變的風險就增加 64%。此外，TIR <10%的參與者中有 27%出現微量白蛋白尿，而 TIR ≥70%的參與者中僅有 3%。雖然這項研究強調了 TIR 與微血管併發症之間的關聯，但數據是基於有限的七點指尖採血測量，這可能無法完全捕捉長期的 TIR 趨勢。

A study of 3262 people with type 2 diabetes found that reduced TIR was linked to increased diabetic retinopathy severity, but when adjusted for HbA1c, no significant difference was observed. ⁷⁴ However, reduced TIR remained significantly associated with the degree of microalbuminuria, even after adjusting for HbA1c. Unlike the previous study that estimated TIR from blood glucose measurements, this study used real‐time CGM for 3 days. Shah et al.’s 7‐year longitudinal analysis confirmed the association between TIR and incident diabetic retinopathy. ⁷⁵ As outlined in a recent systematic review by Yapanis et al., other studies have also demonstrated higher TIR was associated with reduced risk of albuminuria, retinopathy, cardiovascular disease mortality, all‐cause mortality and abnormal carotid intima‐media thickness. ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ The association between TIR and both microvascular and macrovascular complications is becoming increasingly established and has led to increasing recognition as an important outcome measure in diabetes research, which has been well summarized in a commentary by Beck. ⁸⁰

一項針對 3262 名第二型糖尿病患者的研究發現，時間在範圍內（TIR）降低與糖尿病視網膜病變嚴重程度增加有關，但在調整 HbA1c 後，未觀察到顯著差異。然而，即使在調整 HbA1c 後，TIR 降低仍與微量白蛋白尿的程度顯著相關。與先前從血糖測量估計 TIR 的研究不同，本研究使用了為期 3 天的即時連續血糖監測（CGM）。Shah 等人的 7 年縱向分析證實了 TIR 與新發糖尿病視網膜病變之間的關聯。正如 Yapanis 等人最近的系統性回顧中所概述的，其他研究也顯示較高的 TIR 與白蛋白尿、視網膜病變、心血管疾病死亡率、全因死亡率和頸動脈內膜中層厚度異常的風險降低有關。TIR 與微血管和大血管併發症之間的關聯日益確立，並日益被認可為糖尿病研究中的重要結果指標，這在 Beck 的評論中已得到很好的總結。

4.2.3. Benefits of other CGM metrics reported along with TIR
4.2.3. 與時間在範圍內（TIR）一同報告的其他連續血糖監測（CGM）指標的益處

TIR correlates poorly with metrics related to hypoglycaemia risk such as TBR and CV. The international consensus statement by Battelino et al. ⁶⁴ recommends that all CGM data should be included in the final analysis. Reporting TIR along with metrics of hypoglycaemia, including Level 1 and Level 2 TBR, can be valuable especially in trials involving populations at risk of hypoglycaemia or interventions that directly reduce glucose such as sulfonylureas therapy, exercise or insulin.

TIR 與與低血糖風險相關的指標（如 TBR 和 CV）相關性較差。Battelino 等人 ⁶⁴ 的國際共識聲明建議所有 CGM 資料都應包含在最終分析中。報告 TIR 以及低血糖指標（包括第 1 級和第 2 級 TBR）可能很有價值，尤其是在涉及低血糖風險人群或直接降低血糖的干預措施（如磺脲類藥物治療、運動或胰島素）的試驗中。

A United Kingdom database of 8655 patients with diabetes reported that 7.3% of people with type 2 diabetes on insulin therapy had at least one episode of severe hypoglycaemia—a comparable figure to people with Type 1 diabetes (7.1%). ⁸¹ An IQVIA publication on a CORE diabetes model simulated clinical outcomes and costs for people with diabetes and demonstrated that an improvement in TIR to >80% and a reduction in hypoglycaemic events by up to 40% can lead to a reduction in costs of $6.7–9.7 billion over 10 years in USA. ⁸² Type 2 diabetes is more prevalent than type 1 diabetes, and including these metrics as part of clinical trials will allow for easier detection of hypoglycaemia and overall improvement in healthcare costs.

英國一項針對 8655 名糖尿病患者的資料庫報告指出，接受胰島素治療的第二型糖尿病患者中，有 7.3% 至少發生過一次嚴重低血糖事件，這與第一型糖尿病患者的比例 (7.1%) 相當。 ⁸¹ IQVIA 發布的一份關於 CORE 糖尿病模型的出版物，模擬了糖尿病患者的臨床結果和成本，並顯示將時間範圍 (TIR) 提高至 80% 以上，以及將低血糖事件減少高達 40%，可在 10 年內為美國節省 67 至 97 億美元的成本。 ⁸² 第二型糖尿病比第一型糖尿病更為普遍，將這些指標納入臨床試驗的一部分，將有助於更容易偵測低血糖，並全面改善醫療保健成本。

There is no consensus on a clinically meaningful TBR measure, which likely depends on an individual’s frailty and comorbidities. ICTR guidelines suggest targets of <4% time in hypoglycaemia (<3.9 mmol/L; 70 mg/dL) and <1% time in severe hypoglycaemia (<3.0 mmol/L; 54 mg/dL). An observational CGM study in people with type 2 diabetes found that 49.1% had at least one hypoglycaemic episode, with 75% being asymptomatic, which would have been missed using HbA1c alone. ⁸³ The 4‐T trial comparing different insulin regimens in people with type 2 diabetes did a subgroup analysis of the frequency of low‐glucose events using CGM with that of self‐reported hypoglycaemic events and found CGM‐detected hypoglycaemia was several folds higher than self‐reported hypoglycaemia and highlighted the under‐reporting and potential hypoglycaemia unawareness in T2D trials. ⁸⁴ Further observational studies have shown CGM metrics including TBR and CV are more predictive of hypoglycaemia compared to HbA1c alone, which does not capture GV well. ⁸⁵ , ⁸⁶ A large observational study showed hypoglycaemia was common at all levels of HbA1c but patients with HbA1c <6% or ≥9% appeared to be at highest risk for severe hypoglycaemia. ⁸⁷ Hypoglycaemia can be associated with unfavourable health outcomes including a higher risk of falls, fractures, cardiovascular events and mortality. ⁸⁷ A recent cross‐sectional study in patients with type 2 diabetes has shown patients on insulin and sulfonylureas, with a HbA1c <7%, had a significantly higher TAR and TBR compared with those not treated with those agents. ⁸⁶ This provides a further advantage in using TIR as an outcome measure, especially for these hypoglycaemia‐inducing agents, given other CGM metrics including TBR are always to be reported along with it.

目前對於臨床上有意義的低血糖時間（Time in Hypoglycaemia, TBR）指標尚未有共識，這可能取決於個別患者的虛弱程度和共病情況。國際糖尿病聯盟（International Diabetes Federation, IDF）的建議目標是低血糖時間（<3.9 mmol/L；70 mg/dL）<4%，嚴重低血糖時間（<3.0 mmol/L；54 mg/dL）<1%。 在一項針對第二型糖尿病患者的連續血糖監測（CGM）觀察性研究中，發現 49.1%的患者至少發生一次低血糖事件，其中 75%為無症狀性，若僅使用糖化血色素（HbA1c）則會忽略這些情況。 ⁸³ 在比較第二型糖尿病患者不同胰島素治療方案的 4-T 試驗中，研究人員利用 CGM 分析了低血糖事件的頻率，並與自我回報的低血糖事件進行比較，結果發現 CGM 偵測到的低血糖事件比自我回報的事件高出數倍，這突顯了第二型糖尿病試驗中低血糖事件的低報率和潛在的低血糖無感情況。 ⁸⁴ 進一步的觀察性研究顯示，與單獨使用 HbA1c 相比，包括 TBR 和血糖變異係數（Coefficient of Variation, CV）在內的 CGM 指標更能預測低血糖，因為 HbA1c 無法良好地捕捉血糖波動（Glycemic Variability, GV）。 ⁸⁵ , ⁸⁶ 一項大型觀察性研究表明，在所有 HbA1c 水平的患者中低血糖都很常見，但 HbA1c <6%或≥9%的患者發生嚴重低血糖的風險似乎最高。 ⁸⁷ 低血糖可能與不利的健康結果相關，包括跌倒、骨折、心血管事件和死亡的風險增加。 ⁸⁷ 近期一項針對第二型糖尿病患者的橫斷面研究顯示，使用胰島素和磺醯尿素類藥物且 HbA1c <7%的患者，其血糖在目標範圍內的時間（Time in Range, TIR）和 TBR 顯著高於未使用這些藥物的患者。 ⁸⁶ 鑑於包括 TBR 在內的其他 CGM 指標總是會與 TIR 一同報告，這進一步顯示了將 TIR 作為結果指標的優勢，特別是對於這些會引起低血糖的藥物。

5. LIMITATIONS OF TIR AS AN OUTCOME MEASURE
5. 時間範圍作為結果指標的限制

TIR as a clinical trial metric does have some limitations. TIR strongly inversely correlates with hyperglycaemia (R = −0.886); however, it does not represent hypoglycaemia. ⁵⁷ Therefore, TIR as a clinical trial outcome metric should provide a robust assessment of chronic complication risk, but not of hypoglycaemia.

TIR 作為臨床試驗指標確實存在一些限制。TIR 與高血糖呈強烈的反向相關（R = −0.886）；然而，它並不代表低血糖。 ⁵⁷ 因此，TIR 作為臨床試驗結果指標，應能提供對慢性併發症風險的穩健評估，但不能評估低血糖。

To address this limitation, Klonoff et al. ⁸⁸ have proposed a Glycaemic Risk Index (GRI) which represents a composite score weighting very high and very low glucose levels that may be used as a clinical trial outcome to assess the risk for chronic complications due to exposure to elevated glucose levels and also the risk for hypoglycaemia. 330 expert diabetologists from six continents were invited to rank a dataset of 14‐day CGM tracings from 225 adults with diabetes using metrics including TBR and TAR to develop this equation. The association of GRI with DKA risk has yet to be defined.

為了解決此限制，Klonoff 等人 ⁸⁸ 提出了「血糖風險指數」(Glycaemic Risk Index, GRI)，這是一個綜合評分，權衡了極高和極低的血糖水平，可用於臨床試驗結果，以評估因暴露於高血糖水平而導致慢性併發症的風險，以及低血糖的風險。來自六大洲的 330 位糖尿病專家被邀請使用包括 TBR 和 TAR 在內的指標，對來自 225 位糖尿病成人為期 14 天的 CGM 記錄數據進行排名，以開發此方程式。GRI 與 DKA 風險的關聯性仍有待定義。

However, even a construct such as GRI cannot detail all of the insights provided by the multiple metrics included in the standardized CGM report required to guide clinical decisions. For example, the ambulatory glucose profile (AGP) will provide unique insights regarding patterns of glycaemia according to the time of day, which are essential to clinical decision‐making. Other metrics, including CV, GMI, TAR and TBR, provide complementary information that can be used to guide further management; however, these are less validated as outcome measures so far. Ultimately, however, even a review of all of the summary metrics included in a standardized report may not be sufficient, and it may be necessary to assess glycaemic patterns on individual days while accounting for the circumstances under which they occur in order to implement fully informed clinical decisions.

然而，即使是像 GRI 這樣的指標，也無法詳述標準化連續血糖監測（CGM）報告中所包含的眾多指標所提供的所有見解，這些指標對於指導臨床決策至關重要。例如，日間血糖輪廓（AGP）能提供關於一天中不同時間血糖模式的獨特見解，這對臨床決策至關重要。其他指標，包括變異係數（CV）、葡萄糖監測指標（GMI）、目標範圍內時間（TAR）和目標範圍外時間（TBR），提供了可供進一步管理參考的補充資訊；然而，到目前為止，這些指標作為結果指標的驗證程度較低。但最終，即使審閱標準化報告中包含的所有摘要指標可能也不夠，為了做出完全知情的臨床決策，可能需要評估個別日子的血糖模式，同時考慮其發生的情況。

An additional advantage of HbA1c as an outcome measure is that it has been internationally standardized, including the measurement, reference system and reporting according to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) standards. ⁸⁹ In contrast, studies have shown there are discrepancies in glycaemic metrics derived from different CGM models, ⁹⁰ , ⁹¹ and there is no standardization available as yet, making this a further limitation.

HbA1c 作為結果指標的另一項優勢是它已經過國際標準化，包括根據國際臨床化學與檢驗醫學聯合會 (IFCC) 標準進行的測量、參考系統和報告。 ⁸⁹ 相較之下，研究顯示來自不同 CGM 型號的血糖指標存在差異， ⁹⁰ 、 ⁹¹ 且目前尚未有標準化，這使其成為另一項限制。

HbA1c as an outcome measure requires a single blood sample that can be readily obtained and is inexpensive to process. In contrast, TIR as an outcome measure incurs a significant cost. A cost‐effectiveness trial in 2018 has shown CGM devices can cost $15.20 USD/day. ⁹² This financial burden is especially pronounced in countries with limited research funding, where the allocation of resources toward advanced technologies may not be feasible. Additionally, smaller‐scale trials or studies conducted by independent researchers often face significant challenges in securing the necessary funding to incorporate CGM into their protocols. These economic barriers not only limit the widespread adoption of TIR as a standard outcome measure but also contribute to disparities in diabetes research and care, potentially excluding underfunded regions and populations from advancements based on this metric. However, the cost‐effectiveness of CGM has been demonstrated in trials, with a threshold of $100,000 per quality‐adjusted life year (QALY) in type 1 diabetes. ⁹² In insulin‐treated type 2 diabetes, CGM offers clinical benefits and favourable economic outcomes, with a UK study reporting an incremental cost‐effectiveness ratio of £3684/QALY. ⁹³ , ⁹⁴ Studies specifically looking at the cost‐effectiveness of CGM over HbA1c for clinical trials are yet to be established. Over time, we can hope that advancements in technology and increased accessibility will drive down the cost of CGM, making its valuable metrics more widely available for research and clinical practice.

HbA1c 作為結果指標，只需要一次即可輕鬆取得且處理成本低廉的血液樣本。相對地，TIR 作為結果指標會產生顯著的成本。2018 年的一項成本效益試驗顯示，CGM 裝置每天的成本可能高達 15.20 美元 ⁹² 。這種經濟負擔在研究經費有限的國家尤其明顯，這些國家可能無法撥出資源用於先進技術。此外，規模較小的試驗或由獨立研究人員進行的研究，在爭取將 CGM 納入其研究方案所需的資金方面，經常面臨重大挑戰。這些經濟障礙不僅限制了 TIR 作為標準結果指標的廣泛採用，也加劇了糖尿病研究和照護的差異，可能使資金不足的地區和人群無法從基於此指標的進展中受益。然而，CGM 的成本效益已在試驗中得到證明，在第一型糖尿病中，每「品質調整生命年」（QALY）的門檻為 100,000 美元 ⁹² 。在接受胰島素治療的第二型糖尿病患者中，CGM 提供了臨床益處和有利的經濟效益，英國一項研究報告的增量成本效益比為每 QALY 3684 英鎊 ⁹³ 、 ⁹⁴ 。目前尚未有專門針對 CGM 相較於 HbA1c 在臨床試驗中的成本效益進行研究。隨著時間的推移，我們期望技術的進步和可及性的提高能降低 CGM 的成本，使其寶貴的指標能更廣泛地用於研究和臨床實踐。

Additional limitations include CGM devices which may not be readily accessible, where sensors and the processing of data is not standardized, and where the generation of a meaningful dataset may take 2 weeks. CGM devices vary in their accuracy particularly on Day 1 post insertion due to local injury at the insertion site, which can induce an inflammatory reaction that reduces local glucose bioavailability. ⁹⁵ The consistent use of a single CGM device with standardized insertion procedures in both control and intervention groups will address these issues.

其他限制包括連續血糖監測儀（CGM）可能不易取得，其感測器和資料處理並未標準化，且產生有意義的資料集可能需要兩週時間。CGM 裝置的準確度各不相同，尤其是在置入後的第一天，因為置入部位的局部損傷可能引起發炎反應，降低局部葡萄糖的生物可用性。 ⁹⁵ 在對照組和介入組中持續使用單一 CGM 裝置並採用標準化的置入程序，將能解決這些問題。

Finally, while there are increasing data, there are no long‐term prospective randomized controlled trials that have validated the association between TIR and diabetes macrovascular or microvascular complications. Given the very close relationship of TIR and HbA1c, it is unlikely that a study such as UKPDS will be repeated with TIR incorporated as an outcome measure. It is more likely that post‐marketing observational analyses using information from the very large platforms to which CGM devices are uploaded will provide confirmatory evidence of the relationship of TIR with chronic complication development.

最後，儘管資料日益增多，但仍沒有長期的前瞻性隨機對照試驗證實時間在範圍內（TIR）與糖尿病大血管或微血管併發症之間的關聯。鑑於 TIR 與糖化血色素（HbA1c）的密切關係，不太可能再進行像 UKPDS 那樣將 TIR 納入結果指標的研究。更有可能的是，利用上傳至大型平台的連續血糖監測（CGM）裝置資訊進行的上市後觀察性分析，將能提供 TIR 與慢性併發症發展之間關係的確切證據。

6. INTERPRETING TIR CHANGES IN CLINICAL TRIALS
6. 臨床試驗中時間範圍（TIR）變化的詮釋

A recent international consensus statement by Batellino et al. provides recommendations on the use of CGM and its metrics in clinical trials for type 1 and type 2 diabetes. ³ They encourage the use of TIR as an outcome measure given it is instantly sensitive to dietary, lifestyle and pharmacological modifications that can be seen in a clinical trial environment as well as the association with diabetes complications as outlined above. Battelino et al. ³ have also made recommendations on the interpretation of clinically meaningful TIR targets and changes in TIR following an intervention (Figure 3). ‘A difference of ≥5% (absolute percentage points) in TIR is considered clinically meaningful for an individual participant in a clinical study’. ³ They based this conclusion on the DCCT trial retrospective analysis of 7‐point blood glucose monitoring study outlined above, that related the change of percentage TIR to a clinically meaningful HbA1c and diabetes complications. ⁷³ They found that the difference in mean TIR between those who developed retinopathy and microalbuminuria and those who did not was 10–12%, corresponding to an HbA1c difference of 1.0–1.4%. Although TIR differences of 5% were not analysed, it is plausible that the international consensus panel chose it as a more conservative measure. In clinical trials, a HbA1c improvement of ≥0.5% with a therapeutic intervention is considered to be clinically significant according to the ADA and NICE guidelines ⁹⁶ , ⁹⁷ and therefore the correlation of HbA1c and TIR found by Vigersky et al., ⁷¹ ≥0.4%–0.5% would correspond to a change in TIR of ~5%. In terms of study populations, a between‐group difference of ≥3% is considered clinically significant, and studies can be adequately powered to detect this. This was based on consensus opinion from the expert panel of the ICTR.

Battelino 等人最近發表了一份國際共識聲明，針對第一型和第二型糖尿病的臨床試驗中連續血糖監測（CGM）及其指標的使用提出建議。 ³ 他們鼓勵使用血糖時間範圍（TIR）作為結果指標，因為它能即時反映飲食、生活方式和藥理學改變，這些改變在臨床試驗環境中均可觀察到，同時也如前所述，與糖尿病併發症相關。Battelino 等人 ³ 也對臨床上有意義的 TIR 目標以及介入後 TIR 的變動（圖 3 ）提出了詮釋建議。 「TIR 相差 ≥5%（絕對百分點）被認為對臨床研究中的個別參與者具有臨床意義。」 ³ 他們的結論是基於上述 DCCT 試驗對七點血糖監測研究的回顧性分析，該分析將 TIR 百分比的變動與臨床上有意義的 HbA1c 和糖尿病併發症聯繫起來。 ⁷³ 他們發現，出現視網膜病變和微量白蛋白尿的患者與未出現的患者之間，平均 TIR 的差異為 10–12%，相當於 HbA1c 的差異為 1.0–1.4%。雖然尚未分析 5% 的 TIR 差異，但國際共識小組選擇它作為一個較保守的指標是合理的。在臨床試驗中，根據 ADA 和 NICE 的指南 ⁹⁶ 、 ⁹⁷ ，治療介入使 HbA1c 改善 ≥0.5% 被認為具有臨床意義，因此 Vigersky 等人 ⁷¹ 發現的 HbA1c 和 TIR 相關性，≥0.4%–0.5% 將對應於約 5% 的 TIR 變動。就研究族群而言，組間差異 ≥3% 被認為具有臨床意義，且研究有足夠的統計檢定力來偵測此差異。這是基於 ICTR 專家小組的共識意見。

FIGURE 3. 圖 3.

Reporting of clinically significant time in range and time below range outcomes in clinical trials – recommendations from the International Consensus of Time in Range (ICTR). Individual difference = ≥5% change in time in range in an individual participant in a study or clinical trial is considered clinically significant. Treatment group difference = ≥3% difference in the time in range between two groups in a clinical trial or study is considered clinically significant.

臨床試驗中臨床意義顯著的「範圍內時間」及「範圍內低時間」結果的報告——來自「範圍內時間國際共識」（ICTR）的建議。個體差異＝研究或臨床試驗中個別參與者「範圍內時間」改變≥5%被認為具有臨床意義。治療組差異＝臨床試驗或研究中兩組間「範圍內時間」差異≥3%被認為具有臨床意義。

Table 1 summarizes recent meta‐analyses and randomized trials using TIR as a primary or secondary outcome. A systematic review and meta‐analysis by Karakasis et al. ¹⁹ of nine randomized trials comparing once‐weekly versus once‐daily insulin analogues found that once‐weekly insulin significantly increased TIR (MD 3.54%, 95% CI 1.56, 5.53; p = 0.005), meeting ICTR’s clinically meaningful threshold (>3%). However, HbA1c reductions (MD 0.13%, 95% CI 0.23, 0.03; p = 0.08) were neither statistically nor clinically significant. ¹⁹ The once‐weekly insulins were associated with higher odds of level 1 hypoglycaemia, an important consideration to make when prescribing this insulin for a higher hypoglycaemia risk population.

表 1 總結了近期使用時間範圍（TIR）作為主要或次要結果的統合分析和隨機試驗。Karakasis 等人 ¹⁹ 對九項比較每週一次與每日一次胰島素類似物的隨機試驗進行了系統性回顧和統合分析，結果發現每週一次胰島素顯著增加了時間範圍（平均差異 3.54%，95% 信賴區間 1.56，5.53；p = 0.005），達到了 ICTR 的臨床意義門檻（>3%）。然而，糖化血色素（HbA1c）的降低（平均差異 0.13%，95% 信賴區間 0.23，0.03；p = 0.08）在統計學上和臨床上均無顯著意義。 ¹⁹ 每週一次的胰島素與第一級低血糖的機率較高有關，這是在為高低血糖風險人群開立此類胰島素時需要考慮的重要因素。

A randomized trial comparing dapagliflozin and gliclazide MR in 135 participants with uncontrolled type 2 diabetes found that dapagliflozin increased TIR by 24.9%, compared to 17.4% in the gliclazide group—a clinically significant 7.5% difference based on ICTR recommendations. ⁴⁸ However, HbA1c showed no significant change from baseline in either group. While TBR was not compared due to most values being zero, incident hypoglycaemic episodes were significantly higher in the gliclazide group (25.0% vs. 2.2%, p = 0.001). The incidence of hypoglycaemia was defined as either at least 15 continuous minutes of CGM readings ≤3.9 mmol/L or participant‐reported hypoglycaemia, which were symptomatic episodes reported at each study visit or additionally measured glucose ≤3.9 mmol/L.

一項針對 135 名未受控制的第二型糖尿病患者進行的隨機試驗，比較達格列淨與瑞格列酮緩釋劑，結果發現達格列淨組的血糖穩定時間（TIR）增加了 24.9%，而瑞格列酮組為 17.4%，根據國際臨床試驗註冊建議，這是一個臨床上顯著的 7.5%差異。 ⁴⁸ 然而，兩組的糖化血色素（HbA1c）相較於基線均無顯著變化。雖然由於大多數數值為零，因此未比較血糖過低時間（TBR），但瑞格列酮組發生低血糖的事件顯著高於達格列淨組（25.0% vs. 2.2%，p = 0.001）。低血糖事件的定義為連續至少 15 分鐘的連續血糖監測（CGM）讀數≤3.9 mmol/L，或患者報告的低血糖，即在每次研究訪視時報告的有症狀的低血糖事件，或額外測得的血糖≤3.9 mmol/L。

Both studies were greater than 3 months in duration, making HbA1c valid to use. The two studies above highlight the ability of TIR as a metric of glycaemic quality to provide a level of precision when assessing exposure to hyperglycaemia above that of HbA1c in addition to the wealth of information provided by other CGM metrics relating to hypoglycaemia, GV and patterns across the diurnal cycle.
兩項研究的持續時間均超過 3 個月，因此使用 HbA1c 是有效的。上述兩項研究突顯了 TIR 作為血糖品質指標的能力，在評估高血糖暴露方面，除了其他與低血糖、血糖變異性（GV）和晝夜週期模式相關的 CGM 指標所提供的豐富資訊外，還能提供比 HbA1c 更高的精確度。

Several trials using TIR as a primary outcome have shown alignment with HbA1c outcomes. A randomized trial of liraglutide in 124 participants with type 2 diabetes on multiple daily insulin injections (MDI) found a significantly higher TIR in the liraglutide group (66.6% vs. 48.3%, p < 0.001) and a corresponding HbA1c reduction (57.8 vs. 68.7 mmol/L, p < 0.001). Time in hypoglycaemia (<3.9 mmol/L) was similar between the groups. ⁴⁹ Another study by Kawaguchi et al. on 36 patients with type 2 diabetes compared insulin degludec/liraglutide and insulin glargine/lixisenatide, used TIR as a primary outcome measure and found no significant differences between groups in TIR or HbA1c. ¹⁵ The SWITCH PRO trial by Goldenberg et al. comparing insulin glargine to insulin degludec in patients with type 2 diabetes and ≥1 hypoglycaemia risk factor reported a slightly higher TIR for degludec (72.1% vs. 70.7% for glargine), with a small but statistically significant HbA1c difference (7.1% vs. 7.2%). ⁴⁴ They also found degludec had a lower nocturnal TBR compared with glargine and significantly lower nocturnal hypoglycaemic episodes. This demonstrates how TIR can provide complementary insights to HbA1c by providing the TBR metric.

幾項以 TIR 為主要結果的試驗顯示與 HbA1c 結果一致。一項針對 124 名接受每日多次胰島素注射（MDI）的第二型糖尿病患者進行的利拉魯肽隨機試驗發現，利拉魯肽組的 TIR 顯著較高（66.6% vs. 48.3%，p < 0.001），HbA1c 相應降低（57.8 vs. 68.7 mmol/L，p < 0.001）。兩組的低血糖時間（<3.9 mmol/L）相似。 ⁴⁹ Kawaguchi 等人對 36 名第二型糖尿病患者進行的另一項研究，比較了胰島素德古替斯/利拉魯肽與甘精胰島素/利西那肽，以 TIR 作為主要結果指標，發現兩組在 TIR 或 HbA1c 方面均無顯著差異。 ¹⁵ Goldenberg 等人進行的 SWITCH PRO 試驗，比較第二型糖尿病且至少有 1 項低血糖風險因子的患者使用甘精胰島素與胰島素德古替斯，結果顯示胰島素德古替斯的 TIR 略高（72.1% vs. 甘精胰島素的 70.7%），HbA1c 有微小但統計學上顯著的差異（7.1% vs. 7.2%）。 ⁴⁴ 他們還發現胰島素德古替斯的夜間 TBR 低於甘精胰島素，且夜間低血糖事件顯著減少。這證明了 TIR 如何透過提供 TBR 指標來提供與 HbA1c 互補的見解。

Recent trials have used TIR as the primary outcome without reporting HbA1c differences. A crossover randomized trial with 24 patients with type 2 diabetes compared the efficacy of insulin degludec/aspart (IDegAsp) and insulin degludec/liraglutide (IDegLira) in managing postprandial glucose. ³⁵ The study found a higher TIR in the IDegLira group (86.3% vs. 76.3%, p = 0.009) and lower postprandial glucose levels at breakfast and lunch, with no significant differences in TBR. The use of CGM allowed for a detailed comparison of postprandial glucose and TIR, offering valuable insights beyond HbA1c. The increasing use of TIR provides additional, clinically significant data on interventions.

近期試驗已將時間範圍（TIR）作為主要結果，但未報告糖化血色素（HbA1c）的差異。一項針對 24 名第二型糖尿病患者的交叉隨機試驗，比較了胰島素 degludec/aspart (IDegAsp) 和胰島素 degludec/liraglutide (IDegLira) 在餐後血糖管理上的療效。該研究發現 IDegLira 組的 TIR 較高（86.3% vs. 76.3%，p = 0.009），且早餐和午餐後的血糖水平較低，而低於目標範圍的時間（TBR）則無顯著差異。連續血糖監測儀（CGM）的使用，使得餐後血糖和 TIR 的詳細比較成為可能，提供了超越 HbA1c 的寶貴見解。TIR 的日益普及，為介入措施提供了額外且具臨床意義的數據。

GMI and TIR can provide complementary insights into glycaemic patterns. Discordance between TIR and GMI should prompt further exploration of the GV and TBR values. For example, Figure 4A shows the ambulatory glucose profile of a case with a reasonable GMI of 7.4% but below target TIR of 48%. Further evaluation of supporting CGM metrics reveals significant GV of 45.5%, including both high (15%) and low (3%) glucose excursions. Unlike HbA1c, GMI is unaffected by hemoglobinopathies or anaemia, and studies in type 1 diabetes have shown good alignment with lab‐measured HbA1c, as long as no major events have influenced blood glucose levels. ⁶² However, other studies have shown it is identical to Hba1c only 19% of time. ⁹⁸ A prospective study looking at GMI in 144 adults with obstructive sleep apnoea and type 2 diabetes not using insulin found only a moderate correlation between HbA1c and GMI (r = 0.68–0.71), with 36%–43% of participants having a ≥0.5 percentage point difference between the metrics. ⁹ This difference needs to be considered to avoid hypoglycaemia, as GMI has not yet been fully validated as an outcome measure or linked to long‐term complications.

葡萄糖監測指標（GMI）和時間範圍（TIR）可以提供對血糖模式的互補性見解。TIR 和 GMI 之間的差異應促使進一步探討葡萄糖變異性（GV）和低於目標範圍的葡萄糖（TBR）數值。例如，圖 4A 顯示了一位葡萄糖監測指標（GMI）為 7.4% 但時間範圍（TIR）低於目標值 48% 的個案的動態葡萄糖曲線。對輔助性連續葡萄糖監測（CGM）指標的進一步評估顯示，其葡萄糖變異性（GV）顯著，達 45.5%，其中包括高血糖（15%）和低血糖（3%）的葡萄糖波動。與糖化血色素（HbA1c）不同，GMI 不受血紅蛋白病變或貧血的影響，且在第一型糖尿病的研究中顯示與實驗室測量的 HbA1c 有良好的對應關係，只要沒有重大事件影響血糖水平 ⁶² 。然而，其他研究顯示其與 HbA1c 相同的時間僅佔 19% ⁹⁸ 。一項針對 144 名患有阻塞性睡眠呼吸中止症且未注射胰島素的第二型糖尿病成人進行的 GMI 前瞻性研究發現，HbA1c 與 GMI 之間僅有中度相關性（r = 0.68–0.71），其中 36%–43% 的參與者在這些指標之間存在 ≥0.5 個百分點的差異 ⁹ 。由於 GMI 尚未完全驗證為結果指標或與長期併發症相關聯，因此需要考慮這種差異以避免低血糖。

FIGURE 4. 圖 4.

Another alternative to TIR is a newer metric named time in tight glucose range (TITR), which is defined as a glucose level between 3.9 and 7.8 mmol/L (70–140 mg/dL) with a target recommendation of >50% of time per day. This range was based on studies in people without diabetes that have shown they spend 96% of their time between 3.9 and 7.8 mmol/L; therefore, it is suggested this would be a more accurate measure of euglycemia. ⁹⁹ This new range is yet to be incorporated into consensus recommendations; however, some studies have shown its correlation with TIR, ¹⁰⁰ , ¹⁰¹ and HbA1c. ¹⁰² A retrospective study of 13 461 individuals with type 1 diabetes using the Medtronic 780G insulin pump reported TITR targets of ∼45%, ∼50% and ∼55%, correlating with GMI estimates of <7.0%, <6.8% and <6.5%, respectively, making >50% a reasonable target. ¹⁰² TITR has been associated with diabetes‐related complications. A recent cross‐sectional analysis of 1067 individuals with type 1 diabetes found that each 10% increase in TITR was linked to a lower risk of microvascular complications (OR 0.762; 95% CI 0.679–0.855; p < 0.001) and stroke, even after adjusting for HbA1c ¹⁰³ This highlights TITR’s potential as a valuable marker for long‐term diabetes outcomes, though its limitations align with those of TIR, as outlined above.
另一個時間範圍（TIR）的替代方案是稱為「緊密血糖範圍時間」（TITR）的新指標，其定義為血糖值介於 3.9 至 7.8 mmol/L（70–140 mg/dL）之間，目標建議為每天超過 50% 的時間。此範圍是基於對沒有糖尿病者的研究，這些研究顯示他們有 96% 的時間血糖值介於 3.9 至 7.8 mmol/L 之間；因此，建議這將是血糖正常（euglycemia）更準確的衡量標準。 ⁹⁹ 這個新範圍尚未納入共識建議；然而，一些研究已顯示其與 TIR、 ¹⁰⁰ 、 ¹⁰¹ 和 HbA1c 的相關性。 ¹⁰² 一項針對 13,461 名第一型糖尿病患者使用 Medtronic 780G 胰島素幫浦的回溯性研究報告指出，TITR 目標值約為 45%、50% 和 55%，分別與 GMI 估計值 <7.0%、<6.8% 和 <6.5% 相關，使得 >50% 成為一個合理的目標。 ¹⁰² TITR 已與糖尿病相關併發症有關。最近一項針對 1067 名第一型糖尿病患者的橫斷面分析發現，TITR 每增加 10%，微血管併發症（OR 0.762；95% CI 0.679–0.855；p < 0.001）和中風的風險就會降低，即使在調整 HbA1c 後也是如此。 ¹⁰³ 這突顯了 TITR 作為長期糖尿病預後指標的潛力，儘管其限制與上述 TIR 的限制一致。

Glycaemic Risk Index (GRI) is another more recent composite metric that can be considered an outcome measure. A benefit of GRI is that it gives more importance to the risk of hypoglycaemia compared to the risk of hyperglycaemia, which is an important component TIR lacks. A recent cohort study by Wang et al. in 1204 adults with type 2 diabetes without diabetic retinopathy found that for each 1 standard deviation increase in GRI, there was a 20% increase in retinopathy. ¹⁰⁴ Further randomized trials and longer‐term studies are required to validate GRI with other microvascular and macrovascular diabetes complications to consider it as a primary outcome measure.

葡萄糖風險指數（Glycaemic Risk Index, GRI）是另一個較新的綜合指標，可被視為一種結果衡量標準。GRI 的優點在於它比高血糖風險更重視低血糖風險，而這正是時間範圍（Time in Range, TIR）所缺乏的重要組成部分。Wang 等人最近一項針對 1204 名患有第二型糖尿病但無糖尿病視網膜病變的成人進行的世代研究發現，GRI 每增加一個標準差，視網膜病變的風險就會增加 20%。 ¹⁰⁴ 需要進一步的隨機試驗和長期研究來驗證 GRI 與其他微血管和大血管糖尿病併發症的關聯性，以便將其視為主要的結果衡量標準。

The final outcome measure to consider is glycaemic variability (GV), which reflects the degree of glucose fluctuation and is measured by %CV. A recent analysis of CGM data from 2559 patients with type 2 diabetes revealed a strong inverse correlation between TIR and estimated HbA1c (eHbA1c) (r = −0.908). However, this relationship was influenced by glycaemic variability (GV). Specifically, in patients with unstable glucose levels (CV >36%), TIR exhibited high variability, suggesting that GV may mediate the relationship between TIR and eHbA1c. ¹⁰⁵ This highlights the potential importance of considering GV in clinical assessments. GV has been strongly associated with the risk of hypoglycaemia, particularly during insulin therapy, ¹⁰⁶ and is linked to an increased risk of adverse cardiovascular outcomes, primarily due to hypoglycemia. ¹⁰⁷ While GV is a useful marker for hypoglycaemia and can be considered alongside TIR for a comprehensive view of overall glycaemic management, it does not effectively capture hyperglycaemia on its own. Additionally, GV has not yet been definitively associated with long‐term diabetes complications, warranting further studies.

最後一個應考慮的結果指標是血糖變異性 (GV)，它反映了血糖波動的程度，並以變異係數 (%CV) 來衡量。最近對 2559 名第二型糖尿病患者的連續血糖監測 (CGM) 資料進行的分析顯示，時間在範圍內 (TIR) 與估計的糖化血色素 (eHbA1c) 之間存在強烈的反向相關性 (r = −0.908)。然而，這種關係受到血糖變異性 (GV) 的影響。具體來說，在血糖水平不穩定的患者 (CV >36%) 中，TIR 表現出高度變異性，這表明 GV 可能介導 TIR 與 eHbA1c 之間的關係。 ¹⁰⁵ 這突顯了在臨床評估中考慮 GV 的潛在重要性。GV 與低血糖風險密切相關，尤其是在胰島素治療期間， ¹⁰⁶ 並且與不良心血管事件風險增加有關，這主要是由於低血糖。 ¹⁰⁷ 雖然 GV 是低血糖的有用指標，並且可以與 TIR 一起考慮以全面了解整體血糖管理，但它本身無法有效捕捉高血糖。此外，GV 尚未與長期的糖尿病併發症明確關聯，因此需要進一步的研究。

7. CONCLUSIONS 7. 結論

We propose that TIR should be considered a primary research outcome for trials in people with type 2 diabetes where CGM is available. Given that the international consensus defines TIR targets similarly for both T1D and T2D, most arguments presented in this manuscript broadly apply to both conditions. TIR offers key advantages: it captures short‐term glycaemic fluctuations, remains reliable in those with hemoglobinopathies or anaemia, supports personalized glycaemic assessment and correlates with HbA1c. Other CGM glycaemic metrics generated simultaneously at no extra cost or effort provide important insights which HbA1c does not. Leading global endocrinology and diabetes associations back its use as a validated outcome measure. As technology advances with less intrusive, more accurate, and less expensive devices, TIR on CGM is poised to become the gold standard for glycaemic assessment, driving better clinical outcomes. However, additional randomized trials are essential to establish its association with diabetes complications and form guidelines for its use in type 2 diabetes research. Other metrics still need validation before they can be widely adopted in diabetes studies.

我們建議，在可使用連續血糖監測（CGM）的第二型糖尿病（T2D）研究中，血糖時間範圍（TIR）應被視為主要的研究結果。鑑於國際共識對第一型糖尿病（T1D）和第二型糖尿病（T2D）的 TIR 目標定義相似，本文提出的論點大多適用於這兩種病症。TIR 具有關鍵優勢：它能捕捉短期的血糖波動，在患有血紅素病變或貧血的患者中仍可靠，支持個人化的血糖評估，並與糖化血色素（HbA1c）相關。其他同時產生的 CGM 血糖指標，無需額外成本或努力，便能提供 HbA1c 無法提供的寶貴見解。全球主要的內分泌學和糖尿病協會均支持其作為已驗證的結果指標。隨著技術進步，設備變得更具侵入性低、準確性高且成本較低，CGM 上的 TIR 有望成為血糖評估的黃金標準，進而推動更好的臨床結果。然而，仍需要額外的隨機試驗來確立其與糖尿病併發症的關聯，並為其在第二型糖尿病研究中的使用制定指南。其他指標在被廣泛採納於糖尿病研究之前，仍需進一步驗證。

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