The ADA and EASD provided detailed guidance about pharmacological approaches to treat hyperglycemia in diabetic patients (55). The figure illustrates a simplified version of these guidelines. Initiation of therapy: Guidelines advocate simultaneous initiation of metformin and lifestyle modification (i.e., promoting weight loss in patients who are overweight or obese). Guidelines also suggest consideration of an option to initiate two-drug combination therapy if the patient’s HbA1c is more than 1.5%–2.0% above the HbA1c target (e.g., patients with HbA1c >8.5%–9.0% if the HbA1c target is 7.0%). Addition of second drug: Many patients experience secondary failure as T2D progresses, and require addition of a second drug. ADA/EASD guidelines recommend one of four drug classes for second-line therapy: DPP4is, GLP1RAs, SGLT2is, or TZDs. Low-cost generic sulfonylureas represent a fifth option if cost considerations are the major concern. Third- and fourth-line drug. If necessary, three- and four-drug combinations can be constructed with additional drugs from among DPP4is, GLP1RAs, SGLT2is, and TZDs in combination with metformin. Many patients will eventually experience severe β cell failure and transition to insulin-dependent physiology requiring therapy with basal insulin. With one important exception, guidance from the ACC, ESC, and AHA resembles that from the ADA/EASD (56–58). Both the ACC and the ESC have advocated for monotherapy with either GLP1RAs or SGLT2is in patients at high risk for atherosclerotic heart disease. However, it is important to emphasize that there is relatively little evidence to support this recommendation as more than 80% of patients in CVOTs with SGLT2is or GLP1RAs were receiving metformin as part of their therapeutic regimens. The ADA/EASD guidelines provide an inclusive list of options allowing physicians and patients considerable freedom to select whichever drug(s) they prefer. Many physicians may want simpler guidelines offering fewer options, such as we propose in Figure 3.