Guidelines from the American Diabetes Association (ADA), the American Association of Clinical Endocrinologists, and the Endocrine Society are very valuable clinical decision-making tools in the management of type 2 diabetes. In navigating these guidelines, the primary factors that we take into account are the degree of hemoglobin A_1C (HbA_1c) lowering that we need to achieve, the presence of comorbidities, and other patient-specific factors that may warrant additional risk factor modification. First-line treatment with metformin is still supported by the ADA, and treatment selection and targets can be set individually from there for each patient.

The first branch point in the decision tree is efficacy in HbA_1c lowering. The need for a greater HbA_1c reduction will influence your choice of agents. If a patient presents with an HbA_1c of 10%, the plan is going to reflect that, potentially with a preference for medications with greater efficacy in glycemic lowering, such as insulin or glucagon-like peptide 1 (GLP-1) receptor agonists. Patients with baseline HbA_1c  levels closer to target may be candidates for medications with low to moderate efficacy, such as dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT2) inhibitors, which result in a mean HbA_1c reduction of less than 1%.

Contemporary guidelines emphasize the consideration of underlying cardiovascular disease, renal disease, and heart failure when making treatment decisions for patients with type 2 diabetes. Based on the available data, the recommendation is to prescribe a GLP-1 receptor agonist or an SGLT2 inhibitor for patients with underlying cardiovascular disease. For those with underlying renal disease, an SGLT2 inhibitor is the preferred agent, given the data on the benefits observed in that patient population. And then, finally, for patients with heart failure, SGLT2 therapy is currently recommended based on the available outcomes data. These treatment recommendations apply to the aforementioned patient populations with established risk factors independent of HbA_1c.

One also must consider and prioritize other patient-specific factors (eg, weight loss, glycemic control, and risk of hypoglycemia) when designing individualized treatment regimens. The benefits of weight loss include improvements in glycemic control, blood pressure, and lipid parameters, among others. Thus, for many of our patients with type 2 diabetes, weight loss is a priority and agents that facilitate weight loss, including metformin, SGLT2 inhibitors, and GLP-1–based therapy, are preferred. Similarly, weight-neutral medications, such as DPP-4 inhibitors, can be considered at this stage. Conversely, it is important to initially steer away from medications that promote weight gain, where possible. These agents include the thiazolidinediones, insulin, and the sulfonylureas. These medications may ultimately be necessary to achieve HbA_1c targets but will fall a bit lower on the list initially.

Other factors may be given higher priorities in specific patient populations. For example, in elderly patients with multiple comorbidities and impairments in cognitive or functional status, hypoglycemic risk should be prioritized above all else. Agents with low hypoglycemic potential include DPP-4 inhibitors or, potentially, GLP-1 receptor agonists or SGLT2 inhibitors. Cost is another important consideration. Many antidiabetic agents are quite expensive, which may present a potential barrier to adherence.  It is important to understand the patient’s ability to pay for their medications and what their insurance plans are going to cover. 

In conclusion, a very delicate balance of several factors should be weighed when determining the appropriate treatment for each individual patient. Treatment choices can be narrowed down after passing through the points of the decision-making tree and, ultimately, after discussions with patients about the risks and benefits of each treatment, which will hopefully lead to a shared decision about what to prescribe next.