Clinical Context
Prediabetes affects approximately 96 million American adults—more than one-third of the adult population—and represents a critical window for diabetes prevention. Without intervention, 5-10% of individuals with prediabetes progress to type 2 diabetes annually, with up to 70% eventually developing the disease. Beyond diabetes risk, prediabetes itself is associated with increased cardiovascular disease, nephropathy, and neuropathy, making early intervention imperative.
Landmark trials like the Diabetes Prevention Program (DPP) demonstrated that intensive lifestyle intervention can reduce diabetes incidence by 58%, while metformin provides a more modest 31% reduction. However, sustaining lifestyle changes long-term remains challenging, and metformin’s effects are primarily seen in younger patients with higher BMI. The emergence of potent anti-obesity medications raises the question of whether pharmacological weight loss could be a more effective and sustainable approach to prediabetes management.
STEP 10 specifically examined semaglutide in adults with both obesity and prediabetes—testing whether this GLP-1 RA could not merely prevent progression to diabetes but actually reverse prediabetes to normal glucose tolerance. The 81% reversion rate observed makes this one of the most striking diabetes prevention results ever reported.
Study Summary (PICO Framework)
Summary:
In adults with obesity and prediabetes, once-weekly semaglutide 2.4 mg with lifestyle counseling for 52 weeks significantly reduced body weight (-13.9% vs -2.7%) and increased reversion to normoglycemia (81% vs 14%) compared to placebo with lifestyle counseling, though it was associated with higher discontinuation due to adverse events (6% vs 1%).
| PICO | Description |
|---|---|
| Population | Adults ≥18 years with obesity (BMI ≥30) and prediabetes (HbA1c 6.0-6.4% or FPG 5.5-6.9 mmol/L). N=207, 71% female, 88% White. |
| Intervention | Semaglutide 2.4 mg subcutaneously once weekly plus lifestyle counseling for 52 weeks, followed by 28-week off-treatment observation. |
| Comparison | Placebo weekly plus identical lifestyle counseling for 52 weeks, with 28-week off-treatment follow-up. |
| Outcome | Weight loss: -13.9% vs -2.7% (p<0.0001). Normoglycemia reversion: 81% vs 14% (OR 19.8, p<0.0001). Discontinuation for AEs: 6% vs 1%. |
Clinical Pearls
1. The 81% reversion to normoglycemia is unprecedented. No previous pharmacological intervention has achieved such high rates of prediabetes reversal. For comparison, the DPP lifestyle intervention achieved approximately 30-40% reversion, and metformin approximately 20-25%. An odds ratio of 19.8 for reversion represents a transformative effect on glucose metabolism.
2. Weight loss of ~14% approaches bariatric surgery territory. The 13.9% mean weight loss exceeds what is typically achieved with lifestyle modification or older anti-obesity medications. This degree of weight loss produces profound metabolic improvements including enhanced insulin sensitivity, reduced hepatic glucose production, and improved beta-cell function.
3. The 28-week off-treatment period reveals critical information. The study included a 28-week observation period after stopping semaglutide. While the published results focus on the 52-week treatment period, this off-treatment phase will inform whether metabolic improvements persist, partially persist, or fully reverse after medication discontinuation—a key question for clinical practice.
4. Adverse event-related discontinuation was higher but manageable. The 6% discontinuation rate due to adverse events (primarily gastrointestinal) is consistent with other semaglutide trials. This means 94% of patients were able to continue therapy, suggesting that for most patients, side effects are tolerable with appropriate management.
Practical Application
Identifying candidates: Screen patients with obesity for prediabetes using HbA1c or fasting plasma glucose. Those with BMI ≥30 and HbA1c 5.7-6.4% (or 6.0-6.4% using this study’s criteria) are potential candidates for semaglutide as a diabetes prevention strategy. Patients with higher HbA1c within the prediabetes range or those with multiple diabetes risk factors may benefit most.
Positioning relative to other interventions: Consider semaglutide for patients who have not achieved adequate weight loss or glycemic improvement with lifestyle modification alone, or for whom intensive lifestyle programs are not accessible or feasible. It can be positioned as an alternative or complement to metformin, with likely superior efficacy for both weight loss and diabetes prevention.
Counseling patients: Explain that semaglutide addresses both obesity and prediabetes simultaneously. Set expectations for ~14% weight loss over one year with high likelihood (~80%) of returning glucose values to normal. Discuss the possibility that long-term, potentially indefinite treatment may be needed to maintain benefits, pending more data on durability after discontinuation.
Practical management: Use standard semaglutide titration (0.25 mg weekly, increasing monthly). Monitor weight, HbA1c, and fasting glucose at 3, 6, and 12 months. If HbA1c returns to normal (<5.7%) and weight loss goals are met, consider whether to continue therapy for weight maintenance or attempt a structured discontinuation trial with close monitoring.
How This Study Fits Into the Broader Evidence
STEP 10 joins STEP 1-8 in the comprehensive semaglutide Phase 3 program, but uniquely focuses on prediabetes as a primary outcome. The findings align with the ADA 2025 Standards of Care, which now recognize GLP-1 RAs as an option for diabetes prevention in high-risk individuals alongside lifestyle modification and metformin.
The results complement the SELECT trial, which showed cardiovascular benefit in patients with obesity and established CVD but without diabetes. Together, these studies position semaglutide as beneficial across the metabolic disease spectrum: primary prevention (STEP 10), cardiovascular risk reduction (SELECT), and established diabetes management (SUSTAIN program).
Cost-effectiveness analyses will be important. While semaglutide is expensive compared to metformin or lifestyle counseling, preventing type 2 diabetes avoids substantial downstream healthcare costs. For patients at highest risk, pharmacological prevention may be economically justified.
Limitations to Consider
The relatively small sample size (n=207), short duration (52 weeks), and limited diversity (88% White) constrain generalizability. The study was not powered for hard outcomes like diabetes incidence over multiple years. The 28-week off-treatment data will be crucial for understanding durability. Additionally, the specific prediabetes criteria used (HbA1c 6.0-6.4%) is slightly higher than the ADA cutoff of 5.7%, which may affect applicability.
Bottom Line
Semaglutide 2.4 mg weekly produces remarkable weight loss (14%) and unprecedented rates of prediabetes reversion to normal glucose tolerance (81%) in adults with obesity and prediabetes. These findings support semaglutide as a powerful tool for diabetes prevention, particularly for high-risk patients who have not succeeded with lifestyle modification alone. The question of long-term durability after treatment discontinuation remains to be fully answered.
Source: Wilding, John P. H., et al. “Efficacy and safety of once-weekly semaglutide 2.4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial.” The Lancet Diabetes & Endocrinology. Read article here.
