SGLT2 Inhibitors Show Stronger Long-Term Blood Sugar Control Than Sulfonylureas

Meta-analysis highlights long-term advantages in type 2 diabetes treatment

Type 2 diabetes mellitus (T2DM) is a chronic disease marked by insulin resistance and progressive β-cell decline. As the condition advances, many patients experience rising blood glucose despite treatment. When metformin alone no longer suffices, clinicians often add another oral drug. Two major options are sodium–glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas (SUs).

Sulfonylureas boost insulin secretion and lower glucose quickly but lose efficacy over time as β-cell function wanes. SGLT2 inhibitors, by contrast, lower blood glucose through urinary glucose excretion—an insulin-independent mechanism. The key question has been which class maintains control better in the long term.

A new systematic review and meta-analysis directly compared the durability of these two drug classes as add-ons to metformin. The study followed PRISMA 2020 guidelines and was registered in PROSPERO.

Study approach

Researchers searched major databases through March 2025, identifying five randomized controlled trials that compared an SGLT2 inhibitor with a sulfonylurea over at least 96 weeks. Participants were adults with T2DM inadequately controlled on metformin.

The included trials evaluated dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, and bexagliflozin against glimepiride or glipizide. The main measure was change in glycated hemoglobin (HbA1c)—a marker of average blood sugar—between intermediate and later study periods. This change-over-time method focused on durability, or the ability of a therapy to sustain its effect after the initial response.

Quality assessment

All studies showed low risk of bias, and the certainty of evidence was rated moderate using GRADE criteria. The limited number of trials was the main reason for downgrading. A random-effects model accounted for between-study variation, and sensitivity analyses confirmed result stability.

As the authors noted, “All included trials were judged to have low risk of bias, and the consistency of direction and magnitude of effect across time windows supports the robustness of the findings.”

Main results: Consistent durability advantage

Across every analyzed time window, SGLT2 inhibitors maintained better HbA1c control than sulfonylureas:

(Negative values favor SGLT2 inhibitors.)

No heterogeneity was detected (I² = 0%), meaning findings were highly consistent across trials. Differences of 0.1–0.3% may appear small but reflect meaningful improvements in long-term glucose stability.

According to the paper, “The consistent direction of benefit across all durability windows suggests a class effect of SGLT2 inhibitors in maintaining glycemic control beyond two years.”

Why it matters

Sustained HbA1c control reduces the need for additional therapies and lowers long-term complication risks. Sulfonylureas often lose effectiveness, leading to dose escalation or treatment switches. Because SGLT2 inhibitors work independently of insulin, they continue to provide glucose reduction even as β-cell function declines.

This study is the first to synthesize head-to-head RCT evidence showing that such mechanistic differences translate into greater long-term stability in blood glucose levels.

Safety observations

Although glycemic durability was the focus, the included RCTs also reported safety outcomes. SGLT2 inhibitors generally caused fewer hypoglycemic episodes and modest weight loss, while sulfonylureas were linked to more hypoglycemia and weight gain—patterns consistent with known class effects.

Strengths and limitations

Strengths

• Inclusion of only randomized, head-to-head trials with long-term follow-up.

• Consistent direction and magnitude of benefit across all analysis windows.

• Transparent quality assessment and sensitivity testing.

Limitations

• Only five eligible trials, with two contributing data beyond 208 weeks.

• All patients were on metformin, so findings may not apply to metformin-intolerant individuals.

• Sulfonylurea titration limits differed among studies.

• Publication bias tests were underpowered due to few trials.

Despite these constraints, sensitivity analyses showed unchanged results when any single study was removed.

Clinical implications

For clinicians, the findings support choosing SGLT2 inhibitors when long-term durability of blood sugar control is a priority. These drugs appear to delay treatment failure compared with sulfonylureas, potentially postponing the need for insulin or other agents.

The authors caution, however, that “durability beyond four years remains uncertain and should be interpreted as exploratory, given the limited number of long-term RCTs.”

Conclusion

This meta-analysis provides solid evidence that SGLT2 inhibitors maintain lower HbA1c levels more effectively than sulfonylureas when added to metformin therapy in type 2 diabetes.

By sustaining glycemic control over two to four years, SGLT2 inhibitors appear to overcome the gradual loss of efficacy typical of sulfonylureas.

As summarized by the authors, “The durability advantage of SGLT2 inhibitors observed in this analysis is likely attributable to their insulin-independent mechanism and consistent efficacy over prolonged therapy.”

The findings encourage both researchers and clinicians to focus not only on how quickly a drug lowers blood glucose, but on how long it can keep those levels stable.

 

The translation of the preceding English text in Chinese:

 

荟萃分析揭示2型糖尿病治疗的长期优势

2型糖尿病（T2DM）是一种以胰岛素抵抗和β细胞功能逐渐下降为特征的慢性疾病。

随着病程进展，许多患者即使接受治疗，血糖仍会逐渐升高。当单用二甲双胍无法维持良好控制时，临床医生通常会加用另一种口服降糖药。最常用的两类药物是钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂和磺脲类（SUs）。

磺脲类通过促进胰岛β细胞分泌胰岛素来迅速降低血糖，但随着β细胞功能衰退，其疗效往往会逐渐减弱。相比之下，SGLT2抑制剂通过促进尿糖排泄降低血糖，其作用机制独立于胰岛素。关键问题在于：哪一类药物在长期治疗中能更好地维持血糖控制？

一项新的系统综述和荟萃分析直接比较了这两类药物作为二甲双胍联合治疗时的“耐久性”差异。该研究遵循PRISMA 2020指南并在PROSPERO注册。

研究方法

研究人员检索了截至2025年3月的主要数据库，最终纳入了5项随机对照试验（RCTs），这些研究均比较了SGLT2抑制剂与磺脲类在至少96周治疗期内的疗效。参与者均为单用二甲双胍控制不佳的成年T2DM患者。

纳入的试验评估了达格列净、恩格列净、卡格列净、厄格列净和贝格列净，与格列美脲或格列吡嗪进行比较。主要结局指标为糖化血红蛋白（HbA1c）的变化——这是平均血糖水平的标准指标——比较中期与后期的差值。这种“随时间变化”的分析方法重点关注疗效持久性，即治疗在初期反应后能否维持效果。

质量评估

所有研究均显示偏倚风险低，依据GRADE标准评定的证据确定性为中等。研究数量有限是降级的主要原因。分析采用随机效应模型以控制研究间差异，敏感性分析显示结果稳定。

作者指出：“所有纳入的试验均被评为低偏倚风险，且在不同时间窗口中效果方向和幅度的一致性支持了结果的稳健性。”

主要结果：SGLT2抑制剂表现出一致的持久优势

在所有分析的时间窗口中，SGLT2抑制剂在HbA1c控制方面均优于磺脲类：

（负值表示SGLT2抑制剂更优。）

未检测到异质性（I² = 0%），说明结果在各试验间高度一致。虽然差值仅为0.1–0.3%，但这反映出临床上有意义的长期血糖稳定性改善。

论文指出：“在所有时间窗口中疗效方向一致，提示SGLT2抑制剂在两年以上的血糖控制中具有类效应优势。”

研究意义

持续稳定的HbA1c控制可减少治疗强化的需求并降低长期并发症风险。磺脲类药物常随时间失效，导致剂量增加或换药。而SGLT2抑制剂由于其作用机制独立于胰岛素，即使β细胞功能下降，仍能维持降糖效果。

这项研究首次综合了头对头RCT证据，表明两类药物在机制上的差异确实带来了长期血糖控制稳定性的提升。

安全性观察

虽然研究重点是血糖控制的持久性，但纳入的RCTs也报告了安全性结果。总体而言，SGLT2抑制剂导致的低血糖事件更少且伴有轻度体重下降，而磺脲类则出现更多低血糖和体重增加——这一趋势与其已知的药物特征一致。

研究优点与局限

优点

• 仅纳入长期随访的随机、头对头对照试验。

• 各时间窗口中疗效方向与幅度一致。

• 质量评估透明，敏感性分析充分。

局限

• 仅有五项合格试验，其中两项提供208周以上数据。

• 所有患者均接受二甲双胍治疗，因此结果不一定适用于不能耐受二甲双胍者。

• 各研究中磺脲类的剂量调整范围不同。

• 由于试验数量有限，发表偏倚检验效能较低。

尽管存在这些限制，敏感性分析显示去除任一研究后结果无变化。

临床意义

对于临床医生而言，当血糖控制的长期稳定性是治疗重点时，这些结果支持选择SGLT2抑制剂。这类药物似乎能延缓治疗失败，相比磺脲类可推迟使用胰岛素或其他药物的时间。

不过，作者也提醒：“四年以上的疗效持久性仍不确定，鉴于长期RCT数量有限，应将相关结果视为探索性结论。”

结论

这项荟萃分析提供了有力证据：在二甲双胍联合治疗的基础上，SGLT2抑制剂比磺脲类更能维持较低的HbA1c水平。

在两至四年的观察期内，SGLT2抑制剂似乎能克服磺脲类药物疗效随时间下降的趋势。

正如作者总结的那样：“本研究观察到的SGLT2抑制剂耐久性优势，可能源于其胰岛素非依赖机制及长期治疗中的持续疗效。”

这些发现提醒研究者和临床医生，不仅要关注药物降糖速度，还应关注其能维持血糖稳定的时间。

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Reference:

Zhouhong Zhan, Jialiang Wang, Nannan Shen, Xinwen Liu, Lihong Wang

Effectiveness of SGLT2 inhibitors compared to sulphonylureas for long-term glycemic control in type 2 diabetes: A meta-analysis.

Biomol Biomed [Internet]. 2025 Jul. 3 [cited 2025 Oct. 9];26(2):285–294.

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12658

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