Traditionally, successful treatment of patients with type 2 diabetes mellitus (DM) has been defined strictly by achievement of targeted glycemic control, primarily using a stepped-care approach that begins with changes in lifestyle combined with oral therapy that is slowly intensified as disease progression advances and β-cell function declines. However, stepped care is often adjusted without regard to the mechanism of hyperglycemia or without long-term objectives. A more comprehensive definition of treatment success in patients with type 2 DM should include slowing or stopping disease progression and optimizing the reduction of all risk factors associated with microvascular and macrovascular disease complications. To achieve these broader goals, it is important to diagnose diabetes earlier in the disease course and to consider use of more aggressive combination therapy much earlier with agents that have the potential to slow or halt the progressive β-cell dysfunction and loss characteristic of type 2 DM. A new paradigm for managing patients with type 2 DM should address the concomitant risk factors and morbidities of obesity, hypertension, and dyslipidemia with equal or occasionally even greater aggressiveness than for hyperglycemia. The use of antidiabetes agents that may favorably address cardiovascular risk factors should be considered more strongly in treatment algorithms, although no pharmacological therapy is likely to be ultimately successful without concomitant synergistic lifestyle changes. Newer incretin-based therapies, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, which appear to have a favorable cardiovascular safety profile as well as the mechanistic possibility for a favorable cardiovascular risk impact, are suitable for earlier inclusion as part of combination regimens aimed at achieving comprehensive treatment success in patients with type 2 DM.