Abstract Background The SARS-CoV-2 outbreak poses a challenge to health care systems due to its high complication rates in patients with cardiometabolic diseases. Here, we identify risk factors and propose a clinical score to predict COVID-19 lethality, including specific factors for diabetes and obesity, and its role in improving risk prediction. Methods We obtained data of confirmed and negative COVID-19 cases and their demographic and health characteristics from the General Directorate of Epidemiology of the Mexican Ministry of Health. We investigated specific risk factors associated to COVID-19 positivity and mortality and explored the impact of diabetes and obesity on modifying COVID-19-related lethality. Finally, we built a clinical score to predict COVID-19 lethality. Results Among the 177 133 subjects at the time of writing this report (May 18, 2020), we observed 51 633 subjects with SARS-CoV-2 and 5,332 deaths. Risk factors for lethality in COVID-19 include early-onset diabetes, obesity, chronic obstructive pulmonary disease, advanced age, hypertension, immunosuppression, and chronic kidney disease (CKD); we observed that obesity mediates 49.5% of the effect of diabetes on COVID-19 lethality. Early-onset diabetes conferred an increased risk of hospitalization and obesity conferred an increased risk for intensive care unit admission and intubation. Our predictive score for COVID-19 lethality included age ≥ 65 years, diabetes, early-onset diabetes, obesity, age < 40 years, CKD, hypertension, and immunosuppression and significantly discriminates lethal from non-lethal COVID-19 cases (C-statistic = 0.823). Conclusions Here, we propose a mechanistic approach to evaluate the risk for complications and lethality attributable to COVID-19, considering the effect of obesity and diabetes in Mexico. Our score offers a clinical tool for quick determination of high-risk susceptibility patients in a first-contact scenario.