Effects of intensive insulin therapy combined with non-insulin antihyperglycemic agents on glycemic control, variability, and metabolic outcomes in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

Abstract

Intensive insulin therapy (IIT) induces clinical remission in newly diagnosed or poorly controlled type 2 diabetes mellitus (T2DM), but is limited by hypoglycemia risk and weight gain. Combining IIT with non-insulin antihyperglycemic agents may mitigate these drawbacks while improving glycemic variability. This review was registered with PROSPERO (CRD42024582974). We searched PubMed, Embase, Cochrane, Web of Science, ClinicalTrials.gov, and Chinese databases (CNKI, VIP, Wanfang, and Chinese Medical Association journals) for randomized controlled trials (RCTs) comparing intensive insulin therapy (IIT) alone with IIT plus metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), or glucagon-like peptide-1 receptor agonists (GLP-1RA) in adults with type 2 diabetes mellitus (T2DM). The primary outcomes were glycemic variability indices, including mean amplitude of glycemic excursions (MAGE), standard deviation of blood glucose (SDBG), and largest amplitude of glycemic excursions (LAGE). Secondary outcomes included fasting plasma glucose (FPG), 2-h postprandial glucose (PPG-2h), mean blood glucose (MBG), glycated hemoglobin (HbA1c), homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), and insulin requirements, including total daily insulin dose (TDD), basal insulin dose, and bolus insulin dose. Time in range (TIR), body weight, hypoglycemia, and gastrointestinal adverse events (GI-AEs) were analyzed as post hoc exploratory outcomes. Thirty-nine RCTs were included. For the primary glycemic-variability outcomes, GRADE assessments indicated that IIT plus DPP-4i likely reduced MAGE (MD −1.39 mmol/L, 95% CI −1.77 to −1.01) and LAGE (MD −1.20 mmol/L, 95% CI −1.66 to −0.75), while IIT plus SGLT2i likely reduced SDBG (MD −0.28 mmol/L, 95% CI −0.44 to −0.11). Evidence was very uncertain for the effects of IIT plus GLP-1RA on MAGE and IIT plus DPP-4i on SDBG. Among secondary outcomes, IIT plus DPP-4i likely reduced FPG (MD −0.44 mmol/L, 95% CI −0.67 to −0.21), while IIT plus GLP-1RA likely reduced HbA1c (MD −0.73%, 95% CI −1.01 to −0.45). IIT plus GLP-1RA, metformin, or SGLT2i may reduce FPG; IIT plus DPP-4i, GLP-1RA, or metformin may reduce PPG-2h; and IIT plus SGLT2i may reduce HbA1c. IIT plus DPP-4i and IIT plus GLP-1RA may also modestly reduce total daily insulin dose. Evidence for the effect of IIT plus SGLT2i on PPG-2h was very uncertain. Among post hoc exploratory outcomes, IIT plus SGLT2i likely increased TIR (MD 8.23 percentage points, 95% CI 4.13 to 12.32), while IIT plus DPP-4i may reduce hypoglycemia risk (RR 0.53, 95% CI 0.31 to 0.91) and IIT plus GLP-1RA may increase GI-AEs (RR 5.28, 95% CI 1.81 to 15.40). Longer-duration IIT plus GLP-1RA may be associated with greater weight loss (MD −3.63 kg, 95% CI −4.94 to −2.32) in a post hoc exploratory subgroup analysis, whereas evidence for the effect of IIT plus SGLT2i on hypoglycemia was very uncertain. Adjunctive non-insulin antihyperglycemic agents may improve glycemic variability and overall glycemic control in adults with T2DM receiving intensive insulin therapy. The most consistent evidence supported reductions in MAGE and LAGE with DPP-4i and in SDBG with SGLT2i. Reductions in FPG and PPG-2h were observed across several drug classes, while HbA1c was reduced with GLP-1RA and SGLT2i. Post hoc analyses suggested improved TIR with SGLT2i, reduced body weight with longer-duration GLP-1RA therapy, a lower risk of hypoglycemia with DPP-4i, and a higher risk of gastrointestinal adverse events with GLP-1RA; however, these exploratory findings should be interpreted cautiously. https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42024582974.