GLP-1 Receptor Agonists for Prediabetes: What the Evidence Actually Shows

Is any GLP-1 receptor agonist approved for prediabetes?

No. The Wegovy label covers chronic weight management in adults with obesity, or overweight plus at least one weight-related comorbid condition, cardiovascular risk reduction in adults with established cardiovascular disease and obesity or overweight, and noncirrhotic MASH with moderate to advanced fibrosis [1]. Foundayo, the oral orforglipron tablet, is labeled only for weight reduction and long-term weight maintenance in adults with obesity, or overweight with a weight-related comorbid condition [2]. Ozempic and Rybelsus are labeled for type 2 diabetes [3]. Prediabetes appears on none of them as an indication.

Eligibility for Wegovy or Foundayo is written in weight terms, not glucose terms [1][2].

What STEP 10 found in people with prediabetes

STEP 10 enrolled adults with obesity and prediabetes. It randomized 207 adults with obesity and prediabetes, 2 to 1, to weekly semaglutide 2.4 mg or placebo for 52 weeks, followed by 28 weeks off treatment, across 30 sites in Canada, Denmark, Finland, Spain and the UK [4]. Entry required a BMI of 30 or higher plus either an HbA1c of 6.0 to 6.4% or a fasting plasma glucose of 5.5 to 6.9 mmol/L, using UK NICE criteria [4].

Participants were a heavy group at baseline: mean weight 111.6 kg, BMI 40.1, HbA1c 5.9%, fasting glucose 5.9 mmol/L, and 71% were women [4].

At week 52, body weight fell 13.9% with semaglutide and 2.7% with placebo; the estimated difference was -11.2 percentage points (95% CI, -13.0 to -9.4; P<0.0001) [4]. Reversion to normoglycemia, defined as an HbA1c below 6.0% and a fasting glucose below 5.5 mmol/L, occurred in 103 of 127 participants (81%) on semaglutide versus 9 of 64 (14%) on placebo (odds ratio 19.8, 95% CI 8.7 to 45.2; P<0.0001) [4]. Serious adverse events occurred in 9% in each group, and no new safety signals were reported [4].

Other prediabetes evidence

STEP 10 randomized 207 people. A 2025 meta-analysis of GLP-1 receptor agonists in children and adolescents included 18 randomized trials with 1,402 participants, of which 1 was in prediabetes (11 were in obesity and 6 in type 2 diabetes) [7]. In adults, a 14-week trial randomized 88 adults with obesity and prediabetes to liraglutide 1.8 mg daily, a 390 kcal/day calorie restriction arm, or sitagliptin 100 mg [5]. Weight loss of 5% or more occurred in 22% on liraglutide, 44% with calorie restriction and 5% on sitagliptin (P=0.02), and visceral fat fell 4.8%, 9.5% and 0% respectively (P=0.04); the investigators concluded that calorie restriction produced greater weight loss and more favorable body composition than liraglutide alone [5].

Prediabetes itself is a moving target. Five different definitions based on HbA1c, fasting glucose and 2-hour glucose cut points are in use [8], and a 2025 review says it is unclear whether interventions help people with impaired fasting glucose or normal body weight, as are the cost-effectiveness and sustainability of pharmacotherapy for prediabetes [9]. Lifestyle change remains the intervention with the strongest prevention evidence, with a 40 to 70% relative risk reduction [6].

What about tirzepatide and orforglipron?

Tirzepatide is a dual GIP and GLP-1 receptor agonist rather than a pure GLP-1 drug [10]. Its pivotal weight trial, SURMOUNT-1, enrolled 2,539 adults with obesity or overweight and excluded people with diabetes; weight fell 15.0%, 19.5% and 20.9% at 5, 10 and 15 mg versus 3.1% on placebo at 72 weeks [11]. In STEP 1, semaglutide 2.4 mg produced 14.9% versus 2.4% on placebo at 68 weeks in 1,961 adults without diabetes [12], and the open-label head-to-head SURMOUNT-5 found -20.2% with tirzepatide versus -13.7% with semaglutide at 72 weeks in 751 adults with obesity and no type 2 diabetes [13]. None of these trials selected participants for prediabetes.

For an oral option, the Foundayo label describes two 72-week trials. In the trial that enrolled 3,127 adults without diabetes, weight fell 7.4%, 8.3% and 11.1% at the 5.5, 9 and 17.2 mg doses versus 2.1% on placebo; the second trial enrolled 1,613 adults with type 2 diabetes [2].

Side effects and label warnings that matter here

Every weight-management GLP-1 product carries a boxed warning for thyroid C-cell tumors seen in rodents, with human relevance undetermined, and is contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [1][2].

The label's pooled weight-management trials for Wegovy 2.4 mg reported nausea in 44% versus 16% on placebo, diarrhea in 30% versus 16%, vomiting in 24% versus 6%, and constipation in 24% versus 11%; 6.8% of treated patients versus 3.2% on placebo stopped permanently because of adverse reactions [1]. Labeled warnings across the class include acute pancreatitis, acute gallbladder disease, acute kidney injury from volume depletion, severe gastrointestinal reactions (the drug is not recommended in severe gastroparesis), serious hypersensitivity, hypoglycemia when combined with insulin or a sulfonylurea, diabetic retinopathy complications in type 2 diabetes, and pulmonary aspiration during general anesthesia or deep sedation [1][2].

The Foundayo label says hypoglycemia has been associated with GLP-1 receptor agonists in adults without type 2 diabetes. In its trial of adults without diabetes, hypoglycemia was not systematically captured, but glucose below 54 mg/dL was reported in 0.6% of treated participants versus none on placebo, with no severe hypoglycemia [2].

On pregnancy, the weight-management labels say to discontinue when pregnancy is recognized, and the Wegovy label says to stop at least 2 months before a planned pregnancy [1]. Tirzepatide and Foundayo labels advise switching to a non-oral contraceptive method or adding a barrier method for 4 weeks and 30 days respectively after starting and after each dose increase [10][2].

What happens when the drug stops

STEP 10 included a 28-week off-treatment period after the 52 weeks of treatment [4]. For weight, STEP 4 randomized 803 adults who had completed a 20-week semaglutide run-in to continue semaglutide or switch to placebo for 48 weeks, and weight changed by -7.9% versus +6.9%, a 14.8-point difference [14].