Objective: To assess the ability of medication-assisted weight loss to prevent diabetes as a function of the baseline weighted Cardiometabolic Disease Staging (CMDS) score. Research Design and Methods We pooled data from 3,040 overweight and obese participants in three randomized controlled trialsdCONQUER, EQUIP, and SEQUELdassessing efficacy and safety of phentermine/topiramate extended release (ER) for weight loss. In these doubleblind phase III trials, overweight/obese adult patients were treated with a lifestyle intervention and randomly assigned to placebo versus once-daily oral phentermine/ topiramate ER. The weighted CMDS score was calculated using baseline quantitative clinical data including waist circumference, blood glucose, blood pressure, and blood lipids. Incident diabetes was defined based on serial measures of fasting glucose, 2-h oral glucose tolerance test glucose, and/or HbA1c. Results: The absolute decrease in 1-year diabetes incidence rates in subjects treated with medication versus placebo was greatest in those with high-risk CMDS scores at baseline (10.43-6.29%), intermediate in those with moderate CMDS risk (4.67-2.37%), and small in the low-risk category (1.51-0.67%). The number of participants needed to treat to prevent one new case of diabetes over a 56-week period was 24, 43, and 120 in those with baselineCMDS scores of≥60, 30-59, and 0-29, respectively. Conclusions: Numbers needed to treat to prevent one case of type 2 diabetes are markedly lower in patients with high-risk scores. CMDS can be used to quantify risk of diabetes in overweight/obese individuals and predict the effectiveness ofweight-loss therapy to prevent diabetes.