Patients with diabetes mellitus (DM) and additional cardiovascular (CV) risk factors are at very high risk for future CV events. This study investigated the efficacy and safety of a proactive, multifactorial CV risk factor management strategy based on single-pill amlodipine/atorvastatin (SPAA) versus continuing physicians' usual care (UC) over 52 weeks in patients with and without DM. Patients with hypertension and >= 3 additional CV risk factors from the Cluster Randomized Usual Care vs Caduet Investigation Assessing Long-Term-Risk (CRUCIAL) trial an open-label, cluster-randomized trial conducted in 19 countries were enrolled and randomized to receive proactive intervention (based on SPAA 5/10 to 10/20 mg) or UC (based on investigators' best clinical judgment). Patients were analyzed according to baseline DM status. Six hundred patients had DM. Patients with DM in the SPAA and UC arms had mean ages of 61.8 and 61.5 years, respectively, and an absolute coronary heart disease (CH D) risk of 25.2% and 21.5%, respectively. Among non-DM patients, mean ages were 58.6 and 59.5 years, respectively, and CHD risk was 16.0% vs 15.7%, respectively. Least-squares mean treatment differences in percentage change from baseline in calculated 10-year Framingham CHD risk were -26.3% vs -27.3% among DM and non-DM patients (adjusted for respective baseline values) (both P < 0.0001). Among DM and non-DM patients, adverse events were reported in 52.8% versus 45.6% in the SPAA and 49.6% versus 41.6% in the UC arms, respectively. This global risk-management approach, simultaneously targeting blood pressure and lipids, was more effective for reducing calculated 10-year Framingham CH D risk than UC in patients with DM. While blood pressure changes were of smaller magnitude among patients with DM, this strategy reduced overall risk to an extent comparable with that observed in non-DM patients. Further studies are thus warranted to study this proactive risk factor intervention on CV or mortality endpoints in patients with and without DM.