Narrative synthesis of RCT, meta-analysis, and real-world data on semaglutide and tirzepatide effects in individuals with prediabetes, covering diabetes prevention and cardiovascular outcomes across SUSTAIN, STEP, SURMOUNT, and SELECT trial datasets. Evaluates both agents as interventions at the prediabetes stage before T2DM onset. Provides the strongest evidence summary for GLP-1 RA prediabetes intervention—establishing that semaglutide and tirzepatide's benefits in weight, glucose normalization, and cardiovascular protection extend to the prediabetes stage where prevention has the greatest population health impact.
Abstract
BACKGROUND: Prediabetes represents an intermediate stage in the dysglycemia continuum, associated with increased cardiometabolic risk but also substantial opportunity for prevention. The aim of this review was to summarize and critically evaluate the available evidence on the effects of semaglutide and tirzepatide in individuals with prediabetes, focusing on diabetes prevention and cardiovascular (CV) outcomes.
METHODS: A narrative synthesis of data from randomized controlled trials, meta-analyses, and real-world studies assessing semaglutide and tirzepatide in people with prediabetes.
RESULTS: Across the STEP 1, STEP 5, and SELECT trials, semaglutide 2.4 mg significantly increased regression to normoglycemia (up to 84 %) and reduced the risk of progression to diabetes compared with placebo. In the SURMOUNT-1 trial, tirzepatide reduced the incidence of diabetes by nearly 90 % (Hazard Ratio: 0.07; p < 0.001), an effect largely mediated by substantial weight loss. Regarding CV outcomes, the SELECT trial, of which 66.4 % of participants had prediabetes, demonstrated a significant reduction in the primary composite endpoint of CV death, nonfatal myocardial infarction, or nonfatal stroke with semaglutide versus placebo (hazard ratio 0.80; 95 % CI: 0.72-0.90). A prespecified analysis showed that CV risk reduction was independent of baseline HbA1c, supporting CV benefit in people with prediabetes. The ongoing SURMOUNT-MMO trial will further clarify the CV effects of tirzepatide in individuals with obesity without diabetes.
CONCLUSION: Semaglutide and tirzepatide markedly increase regression to normoglycemia and reduce progression to diabetes in people with obesity and prediabetes. Semaglutide has also demonstrated CV benefit in SELECT, including among participants with prediabetes. Ongoing outcome data, particularly from SURMOUNT-MMO, will further define the cardioprotective potential of GLP-1-based medicines across the dysglycemia spectrum.