Remission of diabetes is possible with GLP-1 drugs, Italian study confirms

Real-world data from more than 14,000 Italian adults reveal that GLP-1 receptor agonists can induce remission in type 2 diabetes, with a clinically balanced definition linking drug use to reduced cardiovascular and microvascular risks.

Study: Remission of type 2 diabetes after initiation of GLP-1 receptor agonists: incidence, characteristics and outcomes using multiple definitions in an observational study. Image credit: Meteoritka / Shutterstock

In a recent study published in The Lancet Regional Health – Europeinvestigators examined the clinical characteristics, incidence, and outcomes of type 2 diabetes (T2D) remission after initiation of a glucagon-like peptide-1 receptor agonist (GLP-1RA).

T2D is a metabolic disorder that can lead to a substantially high burden without effective intervention due to macrovascular and microvascular complications. The prevalence of T2D has reached pandemic levels and is projected to increase.

Remission of T2D has emerged as a realistic goal, especially with interventions leading to significant weight loss. GLP-1RAs were effective in reducing glucose, cardiovascular and renal risk, and body weight.

The potential for remission of T2D with GLP-1RAs has attracted attention, particularly since the development of dual incretin receptor agonists. Despite the increasing clinical use of GLP-1RAs, evidence regarding the clinical correlates and incidence of T2D remission is limited.

Study Design and Data Sources

In this multicenter Italian study, investigators analyzed clinical characteristics, remission frequency, and outcomes using different definitions of T2D remission after initiation of GLP-1RA. The GLP-1RA for Simplification in Diabetes (GLIMPLES) study retrospectively collected electronic health record data of patients with T2D who started a GLP-1RA between January 2010 and January 2022. The index date corresponded to the first GLP-1RA prescription. Recession was assessed after the index date according to four definitions.

Definitions of diabetes remission

• R1: HbA1c <6.5% for ≥3 months without glucose-lowering drugs.

• R2: Same as R1, but allows continued use of GLP-1RA.

• R3: Same as R1 but without new glucose-lowering drugs compared to baseline.

• R4: Same as R1 regardless of ongoing drug therapy.

Participants were classified as in remission or not based on these definitions. The primary objective was to assess the incidence of remission, while secondary objectives included the assessment of clinical predictors and the comparison of intermediate outcomes and complications between groups.

Clinical Measures and Statistical Analysis

Intermediate endpoints included blood pressure, body weight, HbA1c, urinary albumin to creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Complications assessed included microangiopathy, macroangiopathy, and cardiovascular events. Baseline comparisons used Chi-square and Student’s t tests. Logistic regression examined associations between GLP-1RA type and remission, while Cox proportional hazard models compared time-to-event outcomes.

Participant Profile and GLP-1RA Distribution

A total of 14,141 T2D patients who initiated GLP-1RA therapy were included in the analysis. The average participant was 60 years old with a 10-year history of diabetes, a BMI of 32 kg/m² and a baseline HbA1c of 8.1%. Common standard therapies included metformin, insulin, and sulfonylureas. The GLP-1RAs used were dulaglutide (50.5%), liraglutide (24.9%), semaglutide (12.1%), exenatide (11%) and lixisenatide (1.4%). Almost 25% of participants switched GLP-1RAs during follow-up.

Recession Frequency and Duration

The mean duration of follow-up was four years. Recession occurred in 5.8% (R1), 6.2% (R2), 12.2% (R3) and 18.3% (R4) of participants. Remission time averaged six months across all definitions. Recession lasted longer under R3 (9.3 months) and R4 (10.1 months) than under R1 (6.5 months) and R2 (6.6 months).

Weight Loss and Drug Associations

Mean weight loss varied by GLP-1RA: semaglutide (3.9 kg), exenatide (3.3 kg), dulaglutide (3.1 kg), liraglutide (3 kg), and lixisenatide (2.8 kg). No single GLP-1RA was consistently superior in achieving remission, although dulaglutide showed positive associations with R1-R3 and semaglutide was negatively associated with R1-R2. These differences were not interpreted as evidence of comparative effectiveness due to treatment switching and different periods of availability.

Predictors of remission of type 2 diabetes

Remission was more likely among patients with shorter diabetes duration, higher BMI, fewer complications, and lower initial use of insulin/SGLT2 inhibitors. Subjects who achieved remission demonstrated modest but significant improvements in body weight (–2 kg), HbA1c (–0.9 to –1.0%), blood pressure (–1 to –2 mmHg), and triglycerides (–15 mg/dL) across all remission definitions.

Renal and cardiovascular effects

Changes in eGFR were similar between definitions, but R3 was associated with slower progression of UACR (∼30% less). New-onset microangiopathy was 12-16% lower in participants with R1-R3, suggesting a possible metabolic memory effect. In addition, R3 was associated with fewer cardiovascular events (HR 0.65), although remission was not associated with differences in macroangiopathy.

Implications and predictive value of R3 Definition

Remission of T2D occurred in a significant proportion of GLP-1RA users, with results varying by definition. The R1 definition showed 5.8% recession, while the permissive criteria (R4) reached 18.3%. Among definitions, R3 represented the most balanced measure, offering moderate prevalence (12.2%), longer duration (9.3 months), and improved microvascular and cardiovascular outcomes.

Study Limitations and Interpretation

Limitations included retrospective design, absence of mortality data, lack of event adjudication, potential attrition bias, and non-protocol-driven discontinuation of medication. These factors may influence observed remission rates and outcomes.