1. 治疗目标1. Treatment Goals Glycemic & Cardiometabolic Goals
现代糖尿病管理已从"血糖控制"演化为综合心肾代谢管理 (cardio-renal-metabolic management)。 ADA 2026 强调个体化目标，并优先选择具有心肾保护证据的药物。
Modern diabetes management has evolved from "glycemic control" to comprehensive cardio-renal-metabolic management. ADA 2026 emphasizes individualized targets and prioritizes drugs with proven cardio-renal protection.
| 指标 | 多数成人目标 | 个体化考量 |
|---|---|---|
| Metric | Target for most adults | Individualized considerations |
| HbA1c | < 7.0% | 老年/共病多 <8.0%；新发健康 <6.5%Elderly / multiple comorbidities <8.0%; newly diagnosed and healthy <6.5% |
| 空腹血糖Fasting plasma glucose | 4.4–7.2 mmol/L (80–130 mg/dL) | 避免低血糖Avoid hypoglycemia |
| 餐后 2h 血糖2-hour postprandial glucose | < 10.0 mmol/L (180 mg/dL) | — |
| TIR (CGM) | > 70% (70–180 mg/dL) | 老年 >50%；妊娠 >70% (63–140)Elderly >50%; pregnancy >70% (63–140) |
| TBR (CGM) | < 4% (<70 mg/dL) | 老年 <1%Elderly <1% |
| 血压Blood pressure | < 130/80 mmHg | 合并 CKD/ASCVD 时更严Stricter with comorbid CKD/ASCVD |
| LDL-C | < 1.8 mmol/L (70 mg/dL) | 极高危 <1.4Very high risk <1.4 |
2. T2D 治疗算法（ADA/EASD 2026）2. T2D Treatment Algorithm (ADA/EASD 2026) Treatment Algorithm
2018 年起 ADA/EASD 已转向"以患者为中心"的算法。2026 版进一步强调：
Since 2018, ADA/EASD has shifted toward a "patient-centered" algorithm. The 2026 edition further emphasizes:
- 所有新诊断 T2D 应同步评估 ASCVD/HF/CKD 风险
- 合并 ASCVD、HF 或 CKD → 优先 GLP-1 RA 或 SGLT2i（不论 HbA1c 水平）
- 合并肥胖 → 优先 具有减重证据的 GLP-1 RA / 双激动剂
- 需要强力降糖 → 双联或三联早期联合（不再"阶梯"逐级加药）
- 所有患者均评估代谢性肝病 (MASLD/MASH) 与睡眠呼吸障碍
- All newly diagnosed T2D should be concurrently assessed for ASCVD/HF/CKD risk
- Comorbid ASCVD, HF, or CKD → prioritize GLP-1 RA or SGLT2i (regardless of HbA1c level)
- Comorbid obesity → prioritize GLP-1 RA / dual agonists with weight-loss evidence
- Strong glucose lowering needed → early dual or triple combination (no longer "stepwise" sequential add-on)
- Assess all patients for metabolic liver disease (MASLD/MASH) and sleep-disordered breathing
2026 ADA 标准首次推荐 GLP-1 类药物用于合并肥胖的 1 型糖尿病患者， 同时给出降低低血糖与 DKA 风险的教育指引。
The 2026 ADA Standards for the first time recommend GLP-1 drugs for type 1 diabetes patients with comorbid obesity, along with educational guidance for reducing the risk of hypoglycemia and DKA.
3. 二甲双胍3. Metformin Metformin
地位：T2D 一线口服药 60 余年；价格低、安全性佳；除非禁忌均应保留。
Status: First-line oral agent for T2D for over 60 years; low cost, good safety; should be retained unless contraindicated.
机制：抑制肝脏糖异生（主要通过激活 AMPK 与抑制线粒体甘油磷酸脱氢酶 mGPD）； 改善外周胰岛素敏感性；可能调节肠道菌群（增加 Akkermansia muciniphila）。
Mechanism: Inhibits hepatic gluconeogenesis (mainly via activation of AMPK and inhibition of mitochondrial glycerophosphate dehydrogenase, mGPD); improves peripheral insulin sensitivity; may modulate the gut microbiota (increasing Akkermansia muciniphila).
效力：HbA1c ↓ 1.0–1.5%；体重中性或轻微下降；无低血糖。
Efficacy: HbA1c ↓ 1.0–1.5%; weight neutral or slight reduction; no hypoglycemia.
注意：eGFR < 30 禁用；30–45 减量；胃肠道反应可改用缓释剂型；长期使用监测 B12。
Caution: Contraindicated at eGFR < 30; reduce dose at 30–45; switch to extended-release for gastrointestinal reactions; monitor B12 with long-term use.
4. GLP-1 受体激动剂4. GLP-1 Receptor Agonists GLP-1 Receptor Agonists
机制：激活 GLP-1 受体，葡萄糖依赖性促胰岛素分泌、抑制胰高血糖素、 延缓胃排空、中枢抑制食欲；不依赖血糖的胰外效应包括心血管、神经保护与抗炎。
Mechanism: Activates the GLP-1 receptor, producing glucose-dependent insulin secretion, suppression of glucagon, delayed gastric emptying, and central appetite suppression; glucose-independent extra-pancreatic effects include cardiovascular, neuroprotective, and anti-inflammatory actions.
| 药物 | 给药 | HbA1c ↓ | 减重 | 心血管获益 |
|---|---|---|---|---|
| Drug | Administration | HbA1c ↓ | Weight loss | Cardiovascular benefit |
| 司美格鲁肽 SemaglutideSemaglutide | 每周皮下 / 每日口服Weekly SC / daily oral | 1.5–1.8% | 4–6 kg (注射)；口服较低4–6 kg (injection); lower for oral | ✅ SUSTAIN-6 (MACE↓) |
| 度拉糖肽 DulaglutideDulaglutide | 每周皮下Weekly SC | 1.0–1.5% | 2–3 kg | ✅ REWIND |
| 利拉鲁肽 LiraglutideLiraglutide | 每日皮下Daily SC | 1.0–1.5% | 2–3 kg | ✅ LEADER |
| 艾塞那肽 Exenatide LARExenatide LAR | 每周皮下Weekly SC | 1.0–1.3% | 2–3 kg | 中性 (EXSCEL)Neutral (EXSCEL) |
| 利司那肽 LixisenatideLixisenatide | 每日皮下Daily SC | 0.5–0.9% | 1–2 kg | 中性 (ELIXA)Neutral (ELIXA) |
主要不良反应：胃肠道（恶心、呕吐、腹泻，多数随时间减轻）； 胰腺炎（罕见）；甲状腺 C 细胞肿瘤动物风险（MTC 家族史禁用）。 长期使用关注胆囊事件、注意脱水致 AKI、糖尿病视网膜病变短期恶化（强效降糖效应）。
Main adverse effects: Gastrointestinal (nausea, vomiting, diarrhea, mostly easing over time); pancreatitis (rare); animal risk of thyroid C-cell tumors (contraindicated with a family history of MTC). With long-term use, watch for gallbladder events, AKI from dehydration, and short-term worsening of diabetic retinopathy (from the potent glucose-lowering effect).
GLP-1 RA 已成为 T2D 治疗的"骨干药物"，并正向肥胖、心衰、CKD、MASH、阿尔茨海默症、酒精/物质依赖 等多适应症扩展。下一代 GLP-1 RA 研发方向：①口服小分子（orforglipron 2026 获批）； ②长效（月度甚至季度）；③与肌肉保留剂联合；④微生物代谢产物驱动的内源性 GLP-1 增强。
GLP-1 RA has become a "backbone drug" of T2D treatment and is expanding into multiple indications such as obesity, heart failure, CKD, MASH, Alzheimer's disease, and alcohol/substance dependence. Directions for next-generation GLP-1 RA development: ① oral small molecules (orforglipron approved 2026); ② long-acting (monthly or even quarterly); ③ combination with muscle-preserving agents; ④ enhancement of endogenous GLP-1 driven by microbial metabolites.
5. GLP-1/GIP 双激动剂5. GLP-1/GIP Dual Agonists Dual Agonists
替西帕肽 (Tirzepatide, 商品名 Mounjaro/Zepbound)： 唯一获批的 GLP-1/GIP 双重激动剂。每周一次皮下注射。
Tirzepatide (brand names Mounjaro/Zepbound): The only approved GLP-1/GIP dual agonist. Once-weekly subcutaneous injection.
- HbA1c ↓ 2.0–2.4%（SURPASS 系列 1–5）
- 减重达 15–20%（SURMOUNT 系列），优于司美格鲁肽 (SURMOUNT-5 直接对比)
- 2024 FDA 批准用于 OSA；心血管结局试验（SURPASS-CVOT）2025 年读出
- HbA1c ↓ 2.0–2.4% (SURPASS 1–5 series)
- Weight loss of 15–20% (SURMOUNT series), superior to semaglutide (SURMOUNT-5 head-to-head)
- FDA approved for OSA in 2024; cardiovascular outcomes trial (SURPASS-CVOT) read out in 2025
机制：GIP 与 GLP-1 协同促进胰岛素分泌、改善脂肪组织功能；GIP 可能逆转 GLP-1 致恶心的不良反应。
Mechanism: GIP and GLP-1 synergistically promote insulin secretion and improve adipose tissue function; GIP may reverse the nausea adverse effect caused by GLP-1.
6. SGLT2 抑制剂6. SGLT2 Inhibitors SGLT2 Inhibitors
机制：抑制肾近曲小管 SGLT2，减少葡萄糖与钠的重吸收，引起糖尿、轻度利尿、 血压下降。心肾保护并非单纯降糖效应，而与血流动力学（渗透性利尿、近端肾小管钠/水排泄）、 肾小管-肾小球反馈、心肌能量代谢转向酮体氧化等有关。
Mechanism: Inhibits SGLT2 in the renal proximal convoluted tubule, reducing reabsorption of glucose and sodium, causing glycosuria, mild diuresis, and a fall in blood pressure. Cardio-renal protection is not merely a glucose-lowering effect, but is related to hemodynamics (osmotic diuresis, proximal tubular sodium/water excretion), tubuloglomerular feedback, and a shift of myocardial energy metabolism toward ketone body oxidation.
| 药物 | HbA1c ↓ | 关键试验 | 批准的非糖尿病适应症 |
|---|---|---|---|
| Drug | HbA1c ↓ | Key trials | Approved non-diabetic indications |
| 恩格列净 EmpagliflozinEmpagliflozin | 0.6–0.8% | EMPA-REG / EMPEROR / EMPA-KIDNEY | HFrEF, HFpEF, CKD |
| 达格列净 DapagliflozinDapagliflozin | 0.6–0.8% | DAPA-HF / DAPA-CKD / DELIVER | HFrEF, HFpEF, CKD |
| 卡格列净 CanagliflozinCanagliflozin | 0.7–0.9% | CANVAS / CREDENCE | CKD (合并 T2D)CKD (with T2D) |
| 艾托格列净 ErtugliflozinErtugliflozin | 0.7–0.9% | VERTIS-CV (中性)VERTIS-CV (neutral) | — |
不良反应：泌尿生殖道感染；脱水/低血压；血糖正常型 DKA（围手术期停用 3 天）； 骨折与下肢截肢风险（卡格列净 CANVAS 信号，CREDENCE 未重现）；Fournier 坏疽（罕见但严重）。
Adverse effects: Genitourinary tract infections; dehydration/hypotension; euglycemic DKA (discontinue 3 days perioperatively); risk of fracture and lower-limb amputation (canagliflozin CANVAS signal, not reproduced in CREDENCE); Fournier gangrene (rare but serious).
SGLT2i 已从"降糖药"演化为"心肾代谢综合治疗药"。 DAPA-CKD、EMPA-KIDNEY 等试验确认其在非糖尿病 CKD、HFpEF/HFrEF 中的获益。 2025 年研究进一步探索在肾移植受者、非糖尿病蛋白尿肾病中的作用。 这是跨适应症平台扩张的范本，对新药开发具有重要启示。
SGLT2i has evolved from a "glucose-lowering drug" into a "comprehensive cardio-renal-metabolic therapy". Trials such as DAPA-CKD and EMPA-KIDNEY confirmed its benefit in non-diabetic CKD and HFpEF/HFrEF. Research in 2025 further explored its role in kidney transplant recipients and non-diabetic proteinuric kidney disease. This is a model of cross-indication platform expansion, with important implications for new drug development.
来源：Source: Frontiers Med 2025 — SGLT2i in non-diabetic CKD · SGLT2i in advanced CKD
7. DPP-4 抑制剂7. DPP-4 Inhibitors DPP-4 Inhibitors
机制：抑制二肽基肽酶-4 (DPP-4)，减少内源性 GLP-1 与 GIP 降解。
Mechanism: Inhibits dipeptidyl peptidase-4 (DPP-4), reducing degradation of endogenous GLP-1 and GIP.
药物：西格列汀 sitagliptin、利格列汀 linagliptin、阿格列汀 alogliptin、沙格列汀 saxagliptin、维格列汀 vildagliptin。
Drugs: sitagliptin, linagliptin, alogliptin, saxagliptin, vildagliptin.
特点：口服，无低血糖与体重影响，HbA1c ↓ 0.5–0.8%。心血管中性 (TECOS, EXAMINE, CARMELINA)， 沙格列汀有心衰住院信号 (SAVOR-TIMI)。是不耐受 GLP-1 RA 或老年共病者的备选。
Features: Oral, no hypoglycemia or weight effect, HbA1c ↓ 0.5–0.8%. Cardiovascular neutral (TECOS, EXAMINE, CARMELINA); saxagliptin shows a heart-failure hospitalization signal (SAVOR-TIMI). An option for those intolerant to GLP-1 RA or elderly patients with comorbidities.
8. TZD 与其他口服药8. TZDs and Other Oral Agents TZDs & Others
噻唑烷二酮 TZDs (吡格列酮 Pioglitazone)Thiazolidinediones (TZDs) (Pioglitazone)
PPAR-γ 激动剂，改善胰岛素敏感性。对 MASH 有改善作用（最新指南推荐）。 不良反应：水肿、体重增加、骨折风险、心衰恶化（HFrEF 慎用）。
PPAR-γ agonists that improve insulin sensitivity. Beneficial for MASH (recommended by the latest guidelines). Adverse effects: edema, weight gain, fracture risk, worsening of heart failure (use with caution in HFrEF).
磺脲类 Sulfonylureas (格列美脲、格列齐特)Sulfonylureas (glimepiride, gliclazide)
促胰岛素分泌剂，价格低，强效。低血糖与体重增加是主要不足； 老年与不规律饮食者风险高，逐渐被新一代药物取代。
Insulin secretagogues, low cost, potent. Hypoglycemia and weight gain are the main drawbacks; risk is high in the elderly and those with irregular eating, and they are gradually being replaced by newer-generation drugs.
α-葡萄糖苷酶抑制剂 (阿卡波糖)α-glucosidase inhibitors (acarbose)
抑制小肠刷状缘 α-糖苷酶，延缓碳水化合物吸收。东亚人群效果较好（高碳水饮食）； 胃肠道反应明显。MARCH 试验显示其降糖效果与二甲双胍相当。
Inhibit α-glucosidase at the small-intestinal brush border, slowing carbohydrate absorption. More effective in East Asian populations (high-carbohydrate diets); marked gastrointestinal reactions. The MARCH trial showed its glucose-lowering effect was comparable to metformin.
格列奈类（瑞格列奈、那格列奈）Glinides (repaglinide, nateglinide)
短效胰岛素促泌剂，主要降低餐后血糖。低血糖风险低于磺脲。
Short-acting insulin secretagogues that mainly lower postprandial glucose. Lower hypoglycemia risk than sulfonylureas.
9. 胰岛素治疗9. Insulin Therapy Insulin Therapy
T1D 必需；T2D 在口服药/GLP-1 RA 无效或特定情况下使用。
Essential in T1D; used in T2D when oral agents/GLP-1 RA are ineffective or in specific situations.
| 类别 | 代表 | 起效 | 峰值 | 持续 |
|---|---|---|---|---|
| Category | Examples | Onset | Peak | Duration |
| 超速效 (Ultra-rapid)Ultra-rapid | 赖脯（Lispro-aabc）、门冬（Fiasp）Lispro-aabc, aspart (Fiasp) | 5–15 min | 0.5–1 h | 3–5 h |
| 速效 (Rapid)Rapid | 赖脯、门冬、谷赖Lispro, aspart, glulisine | 10–20 min | 1–2 h | 3–5 h |
| 短效 (Regular)Regular (short-acting) | 人胰岛素 RHuman insulin R | 30 min | 2–4 h | 6–8 h |
| 中效 (NPH)Intermediate (NPH) | 人胰岛素 NHuman insulin N | 1–2 h | 4–10 h | 10–18 h |
| 长效 (Long-acting)Long-acting | 甘精 U100/U300、地特、德谷Glargine U100/U300, detemir, degludec | 1–4 h | 无峰Peakless | 20–>42 h |
| 周制剂 Insulin IcodecWeekly — Insulin Icodec | (部分国家已批)(approved in some countries) | — | — | ≈ 1 周≈ 1 week |
9.1 治疗模式9.1 Treatment regimens
- 基础胰岛素 + 口服药/GLP-1 RA：T2D 加强治疗起步
- 基础-餐时 (Basal-Bolus)：T1D 与晚期 T2D 标准；模拟生理
- 预混胰岛素 (70/30, 75/25)：每日 2 次注射，依从性好但灵活性差
- 持续皮下输注 CSII（胰岛素泵）：T1D 标准选择之一
- 自动胰岛素输送 AID (闭环)：CGM + 算法 + 泵；ADA 2026 列为 T1D 首选
- Basal insulin + oral agents/GLP-1 RA: starting point for intensifying T2D treatment
- Basal-Bolus: standard for T1D and advanced T2D; mimics physiology
- Premixed insulin (70/30, 75/25): twice-daily injections, good adherence but poor flexibility
- Continuous subcutaneous insulin infusion CSII (insulin pump): one of the standard options for T1D
- Automated insulin delivery AID (closed-loop): CGM + algorithm + pump; listed as first choice for T1D in ADA 2026
Medtronic MiniMed 780G · Tandem t:slim X2 with Control-IQ · Omnipod 5 · iLet Bionic Pancreas · Sequel twiist · CamAPS FX (EU/UK)。 五大系统在 TIR > 70% 与 < 2% 低血糖之间取得良好平衡。 Tandem MOBY（体积缩小 50%）将于 2026 年在加拿大上市。
Medtronic MiniMed 780G · Tandem t:slim X2 with Control-IQ · Omnipod 5 · iLet Bionic Pancreas · Sequel twiist · CamAPS FX (EU/UK). The major systems achieve a good balance between TIR > 70% and < 2% hypoglycemia. Tandem MOBY (50% smaller in size) will launch in Canada in 2026.
来源：Source: Omnipod — ADA 2026 AID Guidance · T1 Support — 2025 Tech Updates
10. 联合治疗策略10. Combination Treatment Strategies Combination Strategies
ADA/EASD 共识：早期联合优于序贯加药。常见组合：
ADA/EASD consensus: early combination is superior to sequential add-on. Common combinations:
- Metformin + GLP-1 RA + SGLT2i — 多通路覆盖、心肾保护
- Metformin + 基础胰岛素 + GLP-1 RA — 减少胰岛素剂量与体重增加
- SGLT2i + GLP-1 RA — 协同减重与心肾保护（DURATION-8 等）
- Tirzepatide ± Metformin — 强效降糖与减重
- 胰岛素 + SGLT2i (T1D, 谨慎使用) — 改善血糖变异性，注意 DKA 风险
- Metformin + GLP-1 RA + SGLT2i — multi-pathway coverage, cardio-renal protection
- Metformin + basal insulin + GLP-1 RA — reduces insulin dose and weight gain
- SGLT2i + GLP-1 RA — synergistic weight loss and cardio-renal protection (DURATION-8, etc.)
- Tirzepatide ± Metformin — potent glucose lowering and weight loss
- Insulin + SGLT2i (T1D, use with caution) — improves glycemic variability, watch for DKA risk
11. 心肾保护策略11. Cardio-Renal Protection Strategies Cardio-Renal Protection
关键原则：在 T2D 合并 ASCVD/HF/CKD 时，优先选择已证明心肾获益的药物，独立于 HbA1c 水平。
Key principle: in T2D with comorbid ASCVD/HF/CKD, prioritize drugs with proven cardio-renal benefit, independent of HbA1c level.
| 合并疾病 | 首选药物 | 循证 |
|---|---|---|
| Comorbidity | Preferred drugs | Evidence |
| 动脉粥样硬化性 CVD (ASCVD)Atherosclerotic CVD (ASCVD) | GLP-1 RA (利拉鲁肽/司美/度拉) 或 SGLT2iGLP-1 RA (liraglutide/semaglutide/dulaglutide) or SGLT2i | LEADER, SUSTAIN-6, REWIND, EMPA-REG |
| 心衰 (HFrEF & HFpEF)Heart failure (HFrEF & HFpEF) | SGLT2i (达格、恩格)SGLT2i (dapagliflozin, empagliflozin) | DAPA-HF, EMPEROR, DELIVER |
| CKD (eGFR ≥ 20) | SGLT2i + 非奈利酮 + GLP-1 RASGLT2i + finerenone + GLP-1 RA | CREDENCE, DAPA-CKD, FIDELIO, FLOW |
| MASH / MASLD | GLP-1 RA (司美) ± 吡格列酮；resmetirom (THR-β)GLP-1 RA (semaglutide) ± pioglitazone; resmetirom (THR-β) | STEP-HFpEF, ESSENCE, MAESTRO-NASH |
FLOW 试验（2024）证实司美格鲁肽显著降低 T2D + CKD 患者主要肾事件复合终点 24%， 扩展了 GLP-1 RA 的肾脏获益证据。
The FLOW trial (2024) confirmed that semaglutide significantly reduced the composite primary kidney-event endpoint by 24% in T2D + CKD patients, expanding the evidence for the renal benefit of GLP-1 RA.