During the 2025 Peking University Diabetes Forum & Coastal Long Bridge Symposium on Metabolic Diseases,Professor Gu Nan from the Department of Endocrinology, Peking University First Hospital, delivered a report on the current application of non‑insulin agents, providing clinicians with scientifically sound and practically valuable references.
- Metformin
Although metformin is not yet approved for the treatment of T1DM in China, multiple studies support its adjunctive value in selected populations.A meta-analysis of 12 randomized controlled trials (RCTs) showed that insulin plus metformin reduced daily insulin dose by an average of 1.36 U/day, decreased body weight and low‑density lipoprotein cholesterol (LDL‑C), without increasing the risk of hypoglycemia or diabetic ketoacidosis (DKA).
The international multicenter REMOVAL study further confirmed that in T1DM patients aged ≥40 years with disease duration ≥5 years and multiple cardiovascular risk factors, metformin (2 g/day) for 3 years significantly reduced body weight and LDL‑C, and improved estimated glomerular filtration rate.
A 26‑week RCT published in Nature Communications on November 24 this year also showed that the total daily insulin dose in the metformin group was reduced by 0.1 U/kg/day compared with the placebo group.
Based on such evidence, the Expert Consensus on Off-Label Clinical Use of Glucose-Lowering Agents (2025 Edition) recommends: Monotherapy with metformin is not recommended in T1DM patients.
In LADA patients with C‑peptide ≥0.3 nmol/L, GADA titer <180 U/ml, HbA1c <9%, and no contraindications, metformin plus lifestyle intervention can be used as basic therapy.
Overweight/obese T1DM patients aged ≥10 years may be treated discretionarily with informed consent. - α‑Glucosidase Inhibitors
For LADA patients with relatively preserved islet function, α‑glucosidase inhibitors may be considered as triple therapy based on complications and glycemic control.
In T1DM patients, add‑on acarbose after intensive insulin therapy significantly reduces 2‑hour postprandial blood glucose, short‑acting insulin dosage, and glycemic variability.Compared with insulin alone, acarbose combined with insulin significantly reduces HbA1c by 0.78% and insulin dosage by 2.32 U. - Dipeptidyl Peptidase‑4 Inhibitors (DPP‑4i)
The Guidelines for the Diagnosis and Treatment of Type 1 Diabetes in China (2021 Edition) recommends that T1DM patients with poor glycemic control may receive DPP‑4i combination therapy with informed consent, and DPP‑4i may be used in LADA patients without contraindications.
The Expert Consensus on Off-Label Clinical Use of Glucose-Lowering Agents (2025 Edition) lists DPP‑4i as an optional agent in insulin‑based regimens for T1DM (weak recommendation). - Sodium‑Glucose Cotransporter‑2 Inhibitors (SGLT‑2i)
SGLT‑2i exert glucose‑lowering effects by promoting urinary glucose excretion, and their use in T1DM remains controversial.
Two key trials of dapagliflozin (DEPICT‑1 and DEPICT‑2) enrolled 1646 T1DM patients with insufficient insulin control.The 5 mg/day and 10 mg/day groups achieved additional HbA1c reductions of 0.42% and 0.45% vs placebo, respectively, without increasing severe hypoglycemia, but with a slight increase in DKA.
The InTandem 3 study of sotagliflozin showed that 400 mg/day reduced HbA1c by 0.51%, body weight by 2.98 kg, and systolic blood pressure by 3.5 mmHg, but significantly increased DKA risk.
Dapagliflozin and sotagliflozin are approved in the EU for T1DM patients with BMI ≥27 kg/m² and insufficient insulin control, but not yet in China.
The 2021 Chinese T1DM Guidelines suggest discretionary use in T1DM patients with BMI ≥25 kg/m², poor insulin control, and informed consent; not recommended in children.Strict patient selection is required in clinical practice, avoiding use in patients with insufficient carbohydrate intake or alcohol abuse, with enhanced ketone monitoring. - Glucagon‑Like Peptide‑1 Receptor Agonists (GLP‑1RA)
GLP‑1RA in T1DM are mainly used for weight management in overweight/obese patients.
The ADJUNCT‑1 study showed that add‑on liraglutide (1.8 mg) in adult T1DM patients reduced HbA1c and body weight but increased hypoglycemia and ketosis risk.Combination with anti‑IL‑21 antibody preserved β‑cell function in newly diagnosed T1DM patients.
Recent studies further explored semaglutide combined with automated insulin delivery, which significantly increased time in range and reduced body weight without increasing severe hypoglycemia.
Relevant guidelines specify the scope of GLP‑1RA: 2021 Chinese T1DM Guidelines: recommended for obese T1DM patients (with informed consent) and LADA patients with preserved islet function.
2025 Off‑Label Consensus: weak recommendation for add‑on GLP‑1RA in T1DM patients with overweight/obesity, high cardio‑renal risk, or high insulin requirements. - Calcium Channel Blockers
Verapamil, a traditional calcium channel blocker, has recently been found to exert islet β‑cell protective effects.
An RCT showed that in adult patients with newly diagnosed T1DM, add‑on verapamil for 12 months improved C‑peptide levels at 3 and 12 months vs placebo, with good tolerability.
A study in patients aged 7.5–17.9 years confirmed that verapamil significantly slowed β‑cell function decline at 52 weeks, with C‑peptide levels 30% higher than placebo, and no drug‑related serious adverse events.These findings provide a novel therapeutic target for β‑cell protection in T1DM.
Summary
Insulin remains the core and foundation of T1DM treatment.Residual β‑cell function, obesity, and other factors may justify the use of non‑insulin agents.Metformin, DPP‑4i, SGLT‑2i, GLP‑1RA, calcium channel blockers, etc., show glucose‑lowering, weight‑reducing, or β‑cell protective effects in specific populations.
However, long‑term safety and cost‑effectiveness require further investigation.Clinicians should balance benefits and risks, strengthen glucose monitoring and patient education to improve long‑term prognosis.