Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg as an Add-On to Dose-Reduced Insulin Glargine versus Dose-Titrated Insulin Glargine in People With Type 2 Diabetes and Overweight (SUSTAIN OPTIMIZE).
Adding semaglutide to dose-reduced insulin glargine improves glycaemic control and reduces weight in type 2 diabetes, but watch for gastrointestinal side effects.
Where it sits
this study against the rest of the dulaglutide corpusSummary and findings
The study evaluated the efficacy and safety of once-weekly semaglutide 2.0 mg added to dose-reduced insulin glargine versus dose-titrated insulin glargine in adults with type 2 diabetes and overweight. Over 40 weeks, semaglutide demonstrated superior reductions in HbA1c, body weight, and daily insulin dose, with fewer severe hypoglycaemia events but more gastrointestinal events. The study involved 573 participants and used an open-label, randomised design.
Abstract
<h4>Aims</h4>Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once-weekly semaglutide 2.0 mg as add-on to dose-reduced insulin glargine (Sema+IGlar<sub>reduced</sub>) versus dose-titrated IGlar (IGlar<sub>titrated</sub>) on glycated haemoglobin (HbA<sub>1c</sub>), body weight (BW), daily insulin dose, and participant satisfaction.<h4>Materials and methods</h4>SUSTAIN OPTIMIZE was a 40-week, phase 3b, open-label, randomised study. Adults with T2D, overweight (body mass index ≥ 25 kg/m<sup>2</sup>), and treatment with basal insulin ≤ 40 units/day were randomised 1:1 into Sema+IGlar<sub>reduced</sub> or IGlar<sub>titrated</sub>. The primary endpoint was change in HbA<sub>1c</sub> using a non-inferiority approach. Secondary endpoints assessed superiority of Sema+IGlar<sub>reduced</sub> versus IGlar<sub>titrated</sub> in reducing HbA<sub>1c</sub>, BW, daily insulin dose, and improving Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) scores.<h4>Results</h4>Overall, 573 participants were randomised. Sema+IGlar<sub>reduced</sub> achieved both non-inferiority and superiority versus IGlar<sub>titrated</sub> in HbA<sub>1c</sub> reduction (estimated treatment difference [ETD]: -0.74%; 95% confidence interval [CI<sub>95</sub>]: -0.90, -0.59) and superiority in BW change (ETD: -8.5 kg; CI<sub>95</sub>: -9.5, -7.4), relative daily insulin dose change (ETD: -121.9%; CI<sub>95</sub>: -143.1, -100.6), and DTSQc scores (ETD: 2.6; CI<sub>95</sub>: 1.6, 3.5) (p < 0.0001 for all endpoints). No new safety concerns were identified. Severe hypoglycaemia was reduced (rate ratio: 0.45; CI<sub>95</sub>: 0.23, 0.87; p = 0.02), while gastrointestinal events were higher for Sema+IGlar<sub>reduced</sub> (310 vs. 32 events).<h4>Conclusions</h4>Once-weekly subcutaneous semaglutide 2.0 mg as add-on to dose-reduced IGlar achieved superior reductions in HbA<sub>1c</sub>, BW, and daily insulin dose in people with T2D and overweight, while reducing their risk for severe hypoglycaemia compared to dose-titrated IGlar alone.
Background
Type 2 diabetes management often involves basal insulin, which can lead to adverse effects like hypoglycaemia and weight gain. This study explores whether adding semaglutide, a GLP-1 receptor agonist, to a reduced dose of insulin glargine could improve glycaemic control and reduce these side effects. Understanding the balance between efficacy and safety in such combinations is crucial for optimizing diabetes management.
Methods
This was a 40-week, phase 3b, open-label, randomised study involving 573 adults with type 2 diabetes and a BMI ≥ 25 kg/m². Participants were on basal insulin ≤ 40 units/day and were randomised 1:1 to receive either semaglutide 2.0 mg weekly with dose-reduced insulin glargine or dose-titrated insulin glargine. The primary endpoint was the change in HbA1c, with secondary endpoints including changes in body weight, daily insulin dose, and DTSQc scores.
Results
Sema+IGlarreduced was non-inferior and superior to IGlar titrated in reducing HbA1c (ETD: -0.74%; CI95: -0.90, -0.59) and showed superiority in reducing body weight (ETD: -8.5 kg; CI95: -9.5, -7.4), daily insulin dose (ETD: -121.9%; CI95: -143.1, -100.6), and improving DTSQc scores (ETD: 2.6; CI95: 1.6, 3.5). Severe hypoglycaemia was less frequent (rate ratio: 0.45; CI95: 0.23, 0.87; p=0.02), but gastrointestinal events were more common in the semaglutide group (310 vs. 32 events).
Interpretation
The findings suggest that semaglutide as an add-on to dose-reduced insulin glargine offers superior glycaemic control and weight reduction compared to dose-titrated insulin glargine alone. While the reduction in severe hypoglycaemia is clinically meaningful, the increased gastrointestinal events warrant consideration. The open-label design and the high incidence of gastrointestinal events may limit the generalizability of the results.
Key findings
- ETD for HbA1c reduction: -0.74%; CI95: -0.90, -0.59
- ETD for body weight change: -8.5 kg; CI95: -9.5, -7.4
- ETD for relative daily insulin dose change: -121.9%; CI95: -143.1, -100.6
- ETD for DTSQc scores: 2.6; CI95: 1.6, 3.5
- Rate ratio for severe hypoglycaemia: 0.45; CI95: 0.23, 0.87; p=0.02
- Gastrointestinal events: 310 vs. 32 events
Limitations
- open-label design
- increased gastrointestinal events
- potential bias due to study design
- single study site not reported
- short follow-up for long-term effects