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达格列净和恩格列净在心力衰竭、慢性肾病和2型糖尿病患者中的临床获益、安全性、真实世界证据和指南推荐有什么差异？请按RCT、真实世界研究、系统综述和适用人群整理，并说明药企市场推广表达边界。
达格列净（Dapagliflozin）和恩格列净（Empagliflozin）是两类钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，在心力衰竭（HF）、慢性肾病（CKD）和2型糖尿病（T2D）患者中均显示出显著的临床益处。以下将从随机对照试验（RCT）、真实世界研究、系统综述和适用人群等方面详细阐述这两种药物的临床获益、安全性、真实世界证据和指南推荐，并探讨药企市场推广的表达边界。
临床获益
SGLT2抑制剂通过独特的排糖机制，不仅能改善血糖控制，还能降低体重、血压，并具有重要的心血管和肾脏保护作用 。
1. 心力衰竭（Heart Failure, HF）
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随机对照试验（RCT）
- 达格列净：DAPA-HF试验评估了达格列净在射血分数降低的心力衰竭（HFrEF）患者中的疗效，无论患者是否患有糖尿病，均显著降低了心血管死亡或心衰住院的复合风险 。
- 恩格列净：EMPEROR-Reduced试验评估了恩格列净在HFrEF患者中的疗效，同样显著降低了心血管死亡或心衰住院的复合风险 。
- 荟萃分析：对DAPA-HF和EMPEROR-Reduced两项试验的预设荟萃分析显示，SGLT2抑制剂（包括达格列净和恩格列净）可使全因死亡风险降低13%（HR 0.87），心血管死亡风险降低14%（HR 0.86），心血管死亡或首次心衰住院的复合风险降低26%（HR 0.74），并降低肾脏复合终点风险（HR 0.62）。这些益处在年龄、性别、糖尿病状态、是否使用血管紧张素受体脑啡肽酶抑制剂（ARNI）以及基线eGFR等亚组中保持一致 。
- 心力衰竭伴射血分数保留（HFpEF）：多项RCT的系统回顾和荟萃分析显示，包括恩格列净和达格列净在内的SGLT2抑制剂，可降低HFpEF患者心血管住院的风险，但对心血管原因或其他原因导致的死亡无显著影响 。这些结果独立于基线eGFR、收缩压、房颤、糖尿病、性别、BMI和nt-proBNP水平 。
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真实世界研究
- EVOLUTION HF研究是一项多国观察性研究，发现达格列净在心衰住院后启动的指南指导药物治疗（GDMTs）中，患者依从性高于其他GDMTs，12个月内停药率为23.5% 。
- AGING-HF研究是一项针对老年心衰患者的观察性研究，平均年龄为90岁，其中260名患者接受SGLT2i（恩格列净或达格列净）治疗。结果显示，SGLT2i治疗与全因死亡率降低（HR 0.67）、心衰再住院率降低（HR 0.64）以及复合终点事件降低（HR 0.60）相关 。治疗耐受性良好，停药率低（2.7%）。
- RED-HEART研究是一项多中心、横断面观察性研究，纳入了1923名心衰门诊患者。结果显示，48.1%的患者正在接受SGLT2i治疗。SGLT2i的使用在HFrEF患者中最高（50.6%），在HFpEF患者中为42.0%。在糖尿病合并心衰患者中，SGLT2i使用率达76.6% 。
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系统综述
- SGLT2抑制剂（达格列净和恩格列净）在有或无糖尿病的HFrEF患者中均能降低心血管死亡或心衰住院的复合风险，并改善肾脏结局 。在没有糖尿病的患者中，SGLT2抑制剂也能显著降低心血管死亡或心衰住院的复合风险，主要归因于心衰住院的减少 。
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适用人群
- 指南推荐SGLT2抑制剂（达格列净或恩格列净）作为射血分数降低的心力衰竭（HFrEF）患者的最佳指南指导药物治疗（GDMT）之一 。
- 对于射血分数保留的心力衰竭（HFpEF）患者，SGLT2抑制剂也是最佳指南指导药物治疗的重要组成部分，并且有新兴证据支持矿物质皮质激素拮抗剂和胰高血糖素样肽-1受体激动剂的使用 。
- 在合并高龄和多种合并症的心衰患者中，SGLT2抑制剂也显示出良好的疗效和安全性 。
2. 慢性肾病（Chronic Kidney Disease, CKD）
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随机对照试验（RCT）
- 达格列净：DAPA-CKD试验证明达格列净在CKD患者中具有肾脏保护作用，无论是否合并T2D 。
- 恩格列净：EMPA-KIDNEY试验显示恩格列净在最广泛的肾脏疾病谱中，无论是否合并T2D，均显示出心肾功效 。
- 卡格列净：CREDENCE试验评估了卡格列净在T2D合并肾病患者中的肾脏保护作用，结果显示能降低主要不良心血管事件（MACE）、心衰和肾脏复合终点风险，但伴随下肢截肢和骨折风险增加 。
- 荟萃分析：SGLT2抑制剂被证实可降低肾脏复合终点风险 。基线肾小球滤过率（eGFR）和白蛋白尿程度是心血管和肾脏事件风险最重要的指标，同时也预示着SGLT2抑制剂最大的临床益处 。
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真实世界研究
- 在真实世界研究中，SGLT2抑制剂也显示出肾脏保护效果。一项针对非糖尿病CKD成人患者的研究发现，达格列净或恩格列净治疗与肾功能下降速度减慢相关，且效果独立于基线尿白蛋白肌酐比（UACR）水平 。
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系统综述
- SGLT2抑制剂（恩格列净、达格列净、卡格列净）通过其独特的糖尿作用，降低血压和体重，并影响肾脏血流动力学，激活肾小管球反馈，减少肾小球高滤过，从而发挥肾脏保护作用 。这些药物与急性肾损伤的风险降低相关 。
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适用人群
- 国际指南推荐SGLT2抑制剂作为T2D合并eGFR ≥20 mL/min/1.73m²患者的一线肾脏保护疗法 。
- 对于非糖尿病CKD患者，SGLT2抑制剂也被证实有效，并且在具有广泛肾脏疾病谱的患者中均有益处 。
3. 2型糖尿病（Type 2 Diabetes, T2D）
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随机对照试验（RCT）
- 恩格列净：EMPA-REG OUTCOME试验显示，恩格列净在T2D合并心血管疾病患者中，显著降低了心血管死亡、全因死亡和心衰住院的风险，同时主要心血管事件（MACE）也显著降低14% 。
- 达格列净、卡格列净、恩格列净：这些SGLT2抑制剂作为单药治疗，在不能使用二甲双胍的T2D患者中，均能有效改善血糖控制、促进体重减轻和降低血压 。
- SGLT2抑制剂在伴有心衰或CKD的前驱糖尿病成人中，与安慰剂相比，可显著降低新发糖尿病的风险（相对风险0.79）。达格列净和恩格列净在新发糖尿病风险方面的相对风险分别为0.68和0.87 。
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真实世界研究
- SGLT2抑制剂在T2D患者中的应用广泛，并被证明能提供心肾保护 。然而，观察性研究表明，只有约一半的T2D患者接受了指南推荐的至少每年一次的eGFR和尿白蛋白肌酐比筛查，这阻碍了CKD的早期诊断和SGLT2抑制剂的早期应用 。
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系统综述
- SGLT2抑制剂通过独特的排糖机制，能够有效降低糖化血红蛋白（HbA1c）水平，并带来体重和血压的额外益处 。
- 所有SGLT2抑制剂（达格列净、恩格列净、卡格列净、艾格列净）在三种慢性疾病（T2D、CHFrEF、CKD）中表现出一致的临床效果，并且不同SGLT2抑制剂之间的效果没有显著差异 。
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适用人群
- 对于T2D患者，SGLT2抑制剂作为一线治疗，尤其是在已确诊心血管疾病或有高心血管风险的患者中，应优先考虑使用，以实现血糖控制和心血管保护双重目标 。
- 对于T2D合并CKD的患者，国际指南推荐SGLT2抑制剂作为一线治疗，eGFR≥20 mL/min/1.73m²即可使用 。
安全性
SGLT2抑制剂普遍具有良好的安全性，但伴随一些特定的不良事件。不同SGLT2抑制剂的不良事件概况有所不同，且真实世界中报告的不良事件可能多于临床试验 。
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随机对照试验（RCT）
- 总体安全性：SGLT2抑制剂显著增加了糖尿病酮症酸中毒（RR 2.57）、生殖器感染（RR 3.75）和血容量不足（RR 1.14）的风险 。
- 不良事件趋势：骨折（RR 1.07）、截肢（RR 1.21）和尿路感染（RR 1.07）的风险有增加趋势 。
- 特定SGLT2抑制剂：
- 卡格列净在CANVAS试验中显示，与安慰剂相比，下肢截肢和骨折的风险增加 。
- 恩格列净在EMPA-REG OUTCOME试验中，除了生殖器真菌感染风险增加外，总体严重不良事件发生率较低，包括急性肾损伤风险较低 。
- 达格列净和恩格列净在大型随机试验中的安全性概况在不同慢性疾病和四种SGLT2抑制剂之间保持一致（p > 0.05）。
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真实世界研究
- 真实世界数据表明，SGLT2抑制剂（恩格列净或达格列净）在老年心衰患者中显示出可接受的安全性，尽管泌尿生殖道感染报告频率较高，但治疗停药率很低 。
- 药企警戒研究发现，不同SGLT2抑制剂的副作用谱不同。真实世界中报告的不良事件可能比临床试验中观察到的更广泛 。
- 糖尿病酮症酸中毒（DKA）：SGLT2抑制剂可能会增加糖尿病酮症酸中毒的风险，包括正常血糖性酮症酸中毒（euglycemic DKA）。其机制可能包括胰岛素剂量减少、SGLT2抑制剂促进胰高血糖素分泌以及可能降低酮体肾脏排泄等 。这给临床医生带来了挑战，因为正常血糖水平下的酮症酸中毒可能被忽视，从而延误适当的管理策略 。
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系统综述
- SGLT2抑制剂普遍增加生殖器感染（如真菌感染）和泌尿道感染的风险 。
- 严重低血糖的风险有降低趋势（RR 0.86），急性肾损伤风险显著降低（RR 0.75）。
- 目前没有证据表明，在截肢、尿路感染、生殖器感染、低血糖和糖尿病酮症酸中毒等安全结局方面，不同的SGLT2抑制剂之间存在显著差异 。
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适用人群
- 在使用SGLT2抑制剂时，应监测特定的不良事件，特别是糖尿病酮症酸中毒、生殖器感染和容量不足的风险 。
- 对于老年患者，尽管伴随一些不良事件，但SGLT2抑制剂的总体安全性和耐受性良好 。
- 临床医生在开具SGLT2抑制剂时，应注意患者是否合并酮症酸中毒的易感因素，如近期使用胰岛素、热量摄入减少、大量饮酒、慢性肝病和糖原贮积病等 。
指南推荐
指南普遍推荐SGLT2抑制剂作为心血管疾病、心衰和慢性肾病患者的重要治疗选择。
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心力衰竭
- 射血分数降低的心力衰竭（HFrEF）的最佳指南指导药物治疗（GDMTs）包括血管紧张素受体脑啡肽酶抑制剂（沙库巴曲/缬沙坦）、证据支持的β-受体阻滞剂（比索洛尔、卡维地洛或缓释美托洛尔）、盐皮质激素拮抗剂（螺内酯或依普利酮）以及SGLT2抑制剂（达格列净或恩格列净）。
- 射血分数保留的心力衰竭（HFpEF）的最佳GDMTs包括SGLT2抑制剂，并有新兴证据支持矿物质皮质激素拮抗剂和胰高血糖素样肽-1受体激动剂的使用 。
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慢性肾病
- 国际指南推荐SGLT2抑制剂作为T2D合并eGFR ≥20 mL/min/1.73m²患者的一线治疗，以提供肾脏保护 。
- 对于非糖尿病CKD患者，SGLT2抑制剂也已被证明具有肾脏保护作用，且效果独立于T2D状态 。
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2型糖尿病
- 对于T2D合并已确诊心血管疾病的患者，具有心血管益处的SGLT2抑制剂应优先考虑，即使血糖控制未达标 。
- 如果需要额外的血糖控制，也可考虑使用胰高血糖素样肽-1受体激动剂 。
药企市场推广表达边界
药企在市场推广SGLT2抑制剂（如达格列净和恩格列净）时，必须严格遵守监管规定和科学证据，确保信息的准确性和平衡性，不能夸大疗效或忽略风险。
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基于RCT和系统综述的证据：
- 心血管益处：可以明确宣传SGLT2抑制剂在HFrEF患者中降低心血管死亡和心衰住院的风险 。对于T2D合并心血管疾病患者，可以宣传恩格列净降低心血管死亡、全因死亡和心衰住院的益处 。对于HFpEF患者，可以宣传降低心血管住院风险，但需注意目前证据未显示降低心血管死亡率 。
- 肾脏益处：可宣传SGLT2抑制剂在T2D和非T2D的CKD患者中具有肾脏保护作用，降低肾脏复合终点风险，并减缓eGFR下降速度 。
- 血糖控制和体重/血压：可强调其改善血糖控制、减轻体重和降低血压的额外益处 。
- 作用机制：可解释SGLT2抑制剂通过促进尿糖排泄来降低血糖的独特机制，及其对肾小管球反馈和容量负荷的影响，从而产生心肾保护作用 。
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安全性信息的披露：
- 必须明确告知SGLT2抑制剂会增加糖尿病酮症酸中毒（包括正常血糖性酮症酸中毒）、生殖器感染和血容量不足的风险 。
- 需提及骨折、截肢和尿路感染的风险可能存在增加趋势，特别是卡格列净在部分试验中显示出下肢截肢风险增加 。
- 强调不同SGLT2抑制剂之间的不良事件概况可能存在差异，且真实世界数据可能显示更广泛的不良事件 。
- 提供预防和管理建议：例如，对于糖尿病酮症酸中毒风险，应指导患者和医生识别症状，并注意调整胰岛素剂量等 。
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真实世界证据的引用：
- 可以引用真实世界研究来支持SGLT2抑制剂在更广泛的患者群体中（如老年、多合并症患者）的有效性和安全性 。
- 但需注意真实世界研究可能存在的局限性，如缺乏随机化、混杂因素较多等，避免过度概括或得出因果结论 。
- 可以提及达格列净较高的患者依从性 。
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指南推荐的引用：
- 可以直接引用国内外权威指南对SGLT2抑制剂在HF、CKD和T2D患者中的推荐，以增强药物的临床可信度 。
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避免跨类比较和未经证实的声明：
- 避免在没有头对头RCT证据的情况下，声称某种SGLT2抑制剂优于另一种，因为目前多数系统综述和荟萃分析显示，达格列净和恩格列净在心血管和肾脏结局方面的差异不显著，整体表现出类效应 。虽然有研究提到恩格列净可能在非CKD患者中降低主要终点风险优于艾格列净，但这并非普遍结论，且个体差异较大 。
- 避免暗示SGLT2抑制剂可以完全预防糖尿病或心血管/肾脏疾病的发生，只能声明降低风险或延缓进展 。
- 避免使用模糊或夸大的词语，如“完全安全”、“治愈”等。
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适应症和人群限制：
- 推广时应明确药物的批准适应症，例如，心力衰竭适应症（HFrEF或HFpEF）、慢性肾病适应症、以及特定人群（如T2D患者）。
- 对于前驱糖尿病患者，可以提及SGLT2抑制剂降低新发T2D的风险，但需注意这不是已批准的适应症，且需结合患者是否伴有心衰或CKD等高危因素 。
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教育和支持：
- 药企在推广产品的同时，也应提供充分的患者和医生教育资源，帮助他们更好地理解SGLT2抑制剂的益处和风险，以及如何安全有效地使用这些药物，特别是关于早期CKD诊断和SGLT2抑制剂使用的障碍问题，如筛查不足、医生知识缺乏等 。
通过以上对达格列净和恩格列净在心衰、CKD和T2D患者中的临床获益、安全性、真实世界证据和指南推荐的详细梳理，以及药企市场推广表达边界的探讨，可以全面理解这类药物在临床实践中的应用和推广策略。
References
1Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors.PubMed
Mei Qiu, Liang-Liang Ding, Miao Zhang, et al.
There are no relevant meta-analyses that have assessed the safety of the sodium-glucose transporter 2 (SGLT2) inhibitors in different chronic diseases. We aimed at evaluating the safety of four SGLT2 inhibitors in three chronic diseases by meta-analysis of the large randomized trials of SGLT2 inhibitors. We performed random-effects meta-analysis and carried out subgroup analysis according to type of underlying diseases and type of SGLT2 inhibitors. SGLT2 inhibitors versus placebo significantly reduced the risk of acute kidney injury (RR 0.75, 95% CI 0.66-0.85), and showed the reduced trend in the risk of severe hypoglycemia (RR 0.86, 95% CI 0.71-1.03). SGLT2 inhibitors significantly increased the risks of diabetic ketoacidosis (RR 2.57), genital infection (RR 3.75), and volume depletion (RR 1.14); and showed the increased trends in the risks of fracture (RR 1.07), amputation (RR 1.21), and urinary tract infection (RR 1.07). These effects exhibited by SGLT2 inhibitors were consistent across three chronic diseases (i.e. type 2 diabetes, chronic heart failure, and chronic kidney disease) and four SGLT2 inhibitors (i.e. dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin) (all > 0.05). These findings will guide that specific adverse events are monitored when SGLT2 inhibitors are used in clinical practice.
2Heart Failure Drug Treatment-Inertia, Titration, and Discontinuation: A Multinational Observational Study (EVOLUTION HF).PubMed
Gianluigi Savarese, Takuya Kishi, Orly Vardeny, et al.
BACKGROUND: Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice. OBJECTIVES: This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings. METHODS: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose. RESULTS: Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively. CONCLUSIONS: Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs.
3Guidelines for treating heart failure.PubMed
Michelle M Kittleson
Optimal guideline-directed medical therapy for heart failure with reduced ejection fraction comprises the angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan), an evidence-based beta-blocker (bisoprolol, carvedilol, or sustained-release metoprolol), a mineralocorticoid antagonist (spironolactone or eplerenone), and a sodium-glucose cotransporter-2 inhibitor (dapagliflozin or empagliflozin). Optimal guideline-directed medical therapy for heart failure with preserved ejection fraction comprises a sodium-glucose cotransporter-2 inhibitor with emerging evidence to support the use of a mineralocorticoid antagonist and glucagon-like peptide-1 receptor agonists. This review will summarize the evidence behind the guideline recommendations, the impact of newer trials on management of patients with HF, and strategies for implementation into clinical practice.
4SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.PubMed
Faiez Zannad, João Pedro Ferreira, Stuart J Pocock, et al.
BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim.
5Euglycemic Diabetic Ketoacidosis: A Review.PubMed
Anar Modi, Abhinav Agrawal, Farah Morgan
INTRODUCTION: Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes. It is characterised by the triad of hyperglycemia (blood sugar >250 mg/dl), metabolic acidosis (arterial pH <7.3 and serum bicarbonate <18 mEq/L) and ketosis. Rarely these patients can present with blood glucose (BG) levels of less than 200 mg/dl, which is defined as euglycemic DKA. The possible etiology of euglycemic DKA includes the recent use of insulin, decreased caloric intake, heavy alcohol consumption, chronic liver disease and glycogen storage disorders. DKA in pregnancy has also been reported to present with euglycemia. The recent use of sodium glucose cotransporter 2 (SGLT2) inhibitors has shed light on another possible mechanism of euglycemic DKA. Clinicians may also be misled by the presence of pseudonormoglycemia. CONCLUSION: Euglycemic DKA thus poses a challenge to physicians, as patients presenting with normal BG levels in ketoacidosis may be overlooked, leading to a delay in appropriate management strategies. In this article, we review all the possible etiologies and the associated pathophysiology of patients presenting with euglycemic DKA. We also discuss the approach to diagnosis and management of such patients. Despite euglycemia, ketoacidosis in diabetic patients remains a medical emergency and must be treated in a quick and appropriate manner.
6Cardiovascular Outcomes With Empagliflozin and Dapagliflozin in Patients Without Diabetes.PubMed
Sahib Singh, Aakash Garg, Udaya S Tantry, et al.
Although the cardiovascular (CV) benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes mellitus (DM) are well known, their effects in patients without DM continue to be explored. We provide a meta-analysis of the available evidence. Online databases were searched for randomized controlled trials (RCTs) comparing SGLT2i to placebo/control in patients without DM. The end points of interest were composite CV death/hospitalization for heart failure (HF) with individual components, all-cause death, major adverse CV events, and serious adverse events. Subgroup analysis was performed according to the type of SGLT2i. Pooled odds ratios (OR) and 95% confidence intervals (CI) were generated through a random-effects model. A total of 6 RCTs with 12,984 patients (6,501 in the SGLT2i group and 6,483 in the placebo group) were included, followed over a mean duration of 17.7 months. Four RCTs had patients with HF, 1 with chronic kidney disease, and 1 with myocardial infarction. The mean age was 64 years, 72% of patients were men and mean hemoglobin A1C was 5.7%. As compared with a placebo, SGLT2i treatment was associated with significant reduction in composite CV death or hospitalization for HF (OR 0.77, 95% CI 0.68 to 0.87, p <0.0001), primarily because of a decrease in hospitalization for HF (OR 0.70, 95% CI 0.60 to 0.81, p <0.00001). No significant differences were found pertaining to CV death (OR 0.86, 95% CI 0.74 to 1.01, p = 0.06), all-cause death (OR 0.89, 95% CI 0.71 to 1.11, p = 0.29) and major adverse CV events (OR 0.95, 95% CI 0.68 to 1.32, p = 0.75). Serious adverse events were lower with use of empagliflozin vs placebo. In conclusion, this study shows significant CV benefits in terms of reduction in CV death or hospitalization for HF in patients without DM treated with SGLT2i as compared with placebo. The underlying heterogeneity of patients in terms of co-morbidities (HF, chronic kidney disease, or myocardial infarction) needs to be considered while interpreting the results.
7Pharmacovigilance study for SGLT 2 inhibitors- Safety review of real-world data & randomized clinical trials.PubMed
Karan B Bhanushali, Heena K Asnani, Ambica Nair, et al.
PURPOSE: Despite effectiveness of sodium-glucose cotransporter 2 (SGLT 2) inhibitors, concerns have been raised about the potential side effects of these drugs. Thus, a pharmaco-vigilance study was designed that aims to identify any discrepancies between the reported adverse events & assess the safety profile of SGLT2 inhibitors. METHODS: We studied diabetic ketoacidosis (DKA), euglycemic DKA, amputation, urinary tract infection (UTI), mycotic genital infection & hypotension associated with empagliflozin, dapagliflozin, canagliflozin & ertugliflozin in RCTs and reporting databases. WHO's VigiBase, FAERS, EMA's EudraVigilance & DAEN were thoroughly studied to obtain spontaneously reported real-world adverse events. RESULTS: Different SGLT2 inhibitors exhibit varied side effect profiles. Additionally, the findings suggest that adverse events may be more likely to occur in a broader population in the real world than in a highly inclusive clinical trial subset CONCLUSION: Our study provides comparison of the real world reported adverse events to adverse events reported in the clinical trials studying the efficacy of SGLT 2 inhibitors.
8Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action.PubMed
Leszek Czupryniak, Ofri Mosenzon, Ivan Rychlík, et al.
Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.
9Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation.PubMed
Rhona Johnston, Olalekan Uthman, Ewen Cummins, et al.
BACKGROUND: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. SOURCES: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. METHODS: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. RESULTS: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). LIMITATIONS: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. CONCLUSIONS: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). FUNDING: The National Institute for Health Research Health Technology Assessment programme.
10Development of SGLT1 and SGLT2 inhibitors.PubMed
Timo Rieg, Volker Vallon
Sodium-glucose cotransporters SGLT1 (encoded by SGLT1, also known as SLC5A1) and SGLT2 (encoded by SGLT2, also known as SLC5A2) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.
11Comparison of Effectiveness Among Different Sodium-Glucose Cotransoporter-2 Inhibitors According to Underlying Conditions: A Network Meta-Analysis of Randomized Controlled Trials.PubMed
Ryoma Kani, Atsuyuki Watanabe, Yoshihisa Miyamoto, et al.
BACKGROUND: To investigate the individual profile of each SGLT2 (sodium-glucose cotransoporter-2) inhibitor in patients with different backgrounds. METHODS AND RESULTS: This study included 21 placebo-controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all-cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53-0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56-0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60-0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis. CONCLUSIONS: The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.
12Efficacy and Safety of SGLT2 Inhibitors in Heart Failure: Observational Evidence in Geriatric Patients-AGING-HF.PubMed
Abdelhakim Hacil, Yara Antakly Hanon, Audrey Lacour, et al.
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown beneficial effects in heart failure (HF) management, but data on their use in geriatric populations with high comorbidity remain limited. This observational study aimed to assess the real-world efficacy and safety of SGLT2i in elderly patients with HF. METHODS: This prospective multicenter study included 496 patients hospitalized for acute heart failure across 3 geriatric units. The mean age was 90 years, and the mean Charlson Comorbidity Index score was 8.2. Participants were divided into 2 groups: the SGLT2i group (n=260) receiving SGLT2i (empagliflozin or dapagliflozin) alongside standard HF treatment, and the Control group (n=236) receiving only standard HF treatment. The primary outcomes were all-cause mortality, HF rehospitalizations, and adverse events over 1 year. RESULTS: SGLT2i use was associated with lower risks of all-cause mortality (hazard ratio, 0.67 [95% CI, 0.46-0.98]; =0.031), HF rehospitalization (hazard ratio, 0.64 [95% CI, 0.42-0.97]; =0.037), and the composite outcome (hazard ratio, 0.60 [95% CI, 0.44-0.82]; =0.001) at 1 year, after multivariable adjustment. No significant interaction was observed between left ventricular ejection fraction status and SGLT2i use ( for interaction=0.12). Although urinary and genital infections were more frequently reported in the SGLT2i group, treatment discontinuation remained low (2.7%). CONCLUSIONS: In this elderly population with high comorbidity, SGLT2i therapy was associated with substantial reductions in mortality and HF rehospitalization, and showed good tolerability and an acceptable safety profile.
13Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.PubMed
Hiddo J L Heerspink, Bruce A Perkins, David H Fitchett, et al.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
14Renoprotective effects of sodium-glucose cotransporter-2 inhibitors.PubMed
Hiddo J L Heerspink, Mikhail Kosiborod, Silvio E Inzucchi, et al.
Over the past two years, our understanding of anti-hyperglycemic medications used to treat patients with type 2 diabetes (T2D) has fundamentally changed. Before the EMPA-REG OUTCOME trial, agents used to lower blood glucose were felt to prevent or delay the development of microvascular complications, but were not known to definitively reduce cardiovascular risk or mortality. Previous studies with then novel sodium-glucose cotransport-2 (SGLT2) inhibitors demonstrated improvements in several cardiovascular and renal risk factors, including HbA1c, blood pressure, weight, renal hyperfiltration, and albuminuria. However, as with other antihyperglycemic drugs, it could not be known if these salutary effects would translate into improved cardiorenal outcomes. In the EMPA-REG OUTCOME trial, SGLT2 inhibition with empagliflozin reduced the primary outcome of major adverse cardiovascular events (MACE), while also reducing mortality, hospitalization for heart failure, and progression of diabetic kidney disease. In the CANVAS Program trials using canagliflozin, the rates of the 3-point MACE endpoint, the risk of heart failure and the renal composite endpoint were also reduced, albeit with an increased risk of lower extremity amputation and fracture. As a result, clinical practice guidelines recommend the consideration of SGLT2 inhibition in high-risk patient subgroups for cardiovascular risk reduction. Ongoing primary renal endpoint trials will inform the cardio-metabolic-renal community about how to optimally treat patients with chronic kidney disease - including those with and without diabetes. Our aim is to review the rationale for renal protection with SGLT2 inhibitors, and their current place in the clinical management of patients with kidney disease.
15Class effects of SGLT2 inhibitors on cardiorenal outcomes.PubMed
Aaron Y Kluger, Kristen M Tecson, Andy Y Lee, et al.
BACKGROUND: To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. RESULTS: The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g). CONCLUSIONS: Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.
16Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.PubMed
Afif Nakhleh, Muhammad Abdul-Ghani, Sivan Gazit, et al.
AIM: To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting. METHODS: We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m, who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes. RESULTS: Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m. The mean body mass index was 29.1 ± 5.4 kg/m. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR. CONCLUSION: In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.
17Empagliflozin and other SGLT2 inhibitors in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis.PubMed
Abdulrahman Khaldoon Hamid, AbdulJaber A'Ed Tayem, Sandra Thair Al-Aish, et al.
BACKGROUND: Heart failure (HF) is a highly prevalent disease, among the primary factors contributing to morbidity and death. One of its types is heart failure with preserved ejection fraction (HFpEF) comprising 40%-50% of newly diagnosed HF cases. Despite the high prevalence of HFpEF, there is still a lack of knowledge regarding the best drugs and treatment approaches to be used. However, the sodium-glucose co-transporter 2 (SGLT2) inhibitors could be a promising treatment. OBJECTIVES: To examine SGLT2 inhibitors' effect on hospitalization, cardiovascular death, and estimated glomerular filtration rate (eGFR) in HFpEF patients. SEARCH METHODS: We conducted searches for randomized controlled trials (RCTs) in PubMed, Embase, Scopus, and Web of Science up to July 2024. SELECTION CRITERIA: We chose RCTs that examined the effects of SGLT2 inhibitors and placebo in individuals with higher than 40% ejection fraction (HFpEF). DATA COLLECTION AND ANALYSIS: The methodology for the systematic review and meta-analysis was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. MAIN RESULTS: We included 8 studies with 16,509 participants. Drugs examined in our paper included empagliflozin, dapagliflozin, sotogliflozin, and ertugliflozin. Various outcomes were analyzed in different papers. However, different SGLT2 inhibitors lead to a decreased risk of cardiovascular hospitalization and kidney injury. Our meta-analysis showed a decreased risk of cardiovascular hospitalization but not death due to cardiovascular causes or other causes. These results were regardless of baseline status of eGFR, systolic blood pressure, atrial fibrillation or flutter, diabetes mellitus, sex, body mass index, and nt-proBNP. The included studies were of moderate to high quality. CONCLUSION: For individuals with HFpEF, SGLT2 inhibitors have been proven to be a safe and effective medication. However, more studies are needed for longer durations, reporting adverse events, effects on exercise tolerance, and other secondary outcomes.
18SGLT2 Inhibitors May Predispose to Ketoacidosis.PubMed
Simeon I Taylor, Jenny E Blau, Kristina I Rother
CONTEXT: Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. EVIDENCE ACQUISITION: Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. EVIDENCE SYNTHESIS: SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. CONCLUSIONS: Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.
19Sodium-Glucose Cotransporter 2 Inhibitors and New-onset Type 2 Diabetes in Adults With Prediabetes: Systematic Review and Meta-analysis of Randomized Controlled Trials.PubMed
Yuichiro Mori, O Kenrik Duru, Katherine R Tuttle, et al.
CONTEXT: The preventive effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors for new-onset diabetes was investigated in secondary analyses of several randomized controlled trials (RCTs). However, the results were inconsistent. OBJECTIVE: This work aimed to synthesize available evidence and evaluate whether SGLT2 inhibitors are effective in preventing new-onset diabetes. METHODS: In this systematic review and meta-analysis of RCTs, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched through February 11, 2022. Two independent authors screened the search results and extracted summary data from eligible RCTs (including original and post hoc analyses) comparing SGLT2 inhibitors and placebo for the risk of new-onset diabetes among adults with prediabetes. Meta-analysis was conducted using random-effects models to calculate risk ratios and 95% CIs. RESULTS: We included 4 RCTs with 5655 participants who had prediabetes. Based on the random-effects meta-analysis, SGLT2 inhibitors were significantly associated with a lower risk of new-onset diabetes (relative risk, 0.79; 95% CI, 0.68-0.93). The relative risks of new-onset diabetes in dapagliflozin and empagliflozin were 0.68 (95% CI, 0.52-0.89) and 0.87 (95% CI, 0.72-1.04), respectively (P-for-heterogeneity = .14). The frequency of severe hypoglycemia was not elevated in the SGLT2 inhibitors group compared to the placebo group. CONCLUSION: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of new-onset type 2 diabetes among adults with prediabetes and heart failure or chronic kidney disease. These findings indicate the potential usefulness of SGLT2 inhibitors in preventing diabetes among high-risk populations with prediabetes.
20Real-world data on Empagliflozin and Dapagliflozin use in patients with HEART failure: The RED-HEART study.PubMed
Umut Kocabas, Isil Ergin, Veysel Yavuz, et al.
AIMS: We aimed to determine the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and to identify clinical factors associated with their use in patients with heart failure (HF) in a real-life setting. METHODS: Real-world data on Empagliflozin and Dapagliflozin use in patients with HEART failure: The RED-HEART study is a multicentre, cross-sectional and observational study that included HF patients in the outpatient setting regardless of ejection fraction from 19 cardiology centres between August 2023 and December 2023. RESULTS: The study population consisted of 1923 patients with HF, predominantly men (61.2%), with a median age of 66 (range: 19-101) years. Overall, 925 patients (48.1%) were receiving SGLT2is. Among the study population, 22.1% had HF with preserved ejection fraction, 21.5% had HF with mildly reduced ejection fraction, 56.4% had HF with reduced ejection fraction and the use of SGLT2is was 42.0%, 47.9% and 50.6% in each group, respectively (P = 0.012). The use of SGLT2is was 76.6% in patients with HF and diabetes, 19.8% in patients with HF and chronic kidney disease and 26.8% in patients without diabetes and chronic kidney disease (P < 0.001). Higher education level [odds ratio (OR): 1.80; 95% confidence interval (CI): 1.06-3.05; P = 0.027], higher household income (OR: 3.46; 95% CI: 1.27-9.42; P = 0.015), New York Heart Association functional class IV (OR: 2.72; 95% CI: 1.16-6.35; P = 0.021), diabetes (OR: 9.42; 95% CI: 6.72-13.20; P < 0.001), the use of angiotensin receptor-neprilysin inhibitors (ARNis) (OR: 4.09; 95% CI: 2.39-7.01; P < 0.001), the use of mineralocorticoid receptor antagonists (MRAs) (OR: 2.02; 95% CI: 1.49-2.75; P < 0.001), the use of loop diuretics (OR: 1.62; 95% CI: 1.18-2.22; P = 0.003) and the use of thiazide diuretics (OR: 1.72; 95% CI: 1.30-2.29; P < 0.001) were independently associated with the use of SGLT2is. Conversely, atrial fibrillation (OR: 0.63; 95% CI: 0.45-0.88; P = 0.008), chronic kidney disease (OR: 0.53; 95% CI: 0.37-0.76; P = 0.001), the use of dihydropyridine calcium channel blockers (OR: 0.68; 95% CI: 0.48-0.98; P = 0.042) and the use of statins (OR: 0.67; 95% CI: 0.49-0.91; P = 0.010) were independently associated with the non-use of SGLT2is. CONCLUSIONS: The RED-HEART study provided comprehensive real-world data about implementing SGLT2is in patients with HF. These results suggest that there is a need for organized action and close collaboration between healthcare providers to improve the implementation of SGLT2is, especially in patients with HF with preserved ejection fraction and chronic kidney disease.