What are the stepwise medication treatments for type 2 diabetes?

From the Guidelines

The stepwise medication treatment for type 2 diabetes typically begins with metformin as first-line therapy, and the most recent guidelines from 2024 1 support this approach, emphasizing the importance of individualized treatment goals and patient-centered care. The treatment plan should be reevaluated at regular intervals, every 3–6 months, and adjusted as needed to incorporate specific factors that impact the choice of treatment. Early combination therapy can be considered in adults with type 2 diabetes at treatment initiation to shorten the time to attainment of individualized treatment goals. Some key points to consider when selecting pharmacologic agents include:

• Effect on cardiovascular and renal comorbidities
• Efficacy
• Hypoglycemia risk
• Impact on weight
• Cost and access
• Risk for adverse reactions and tolerability
• Patient preferences If metformin alone fails to achieve target blood glucose levels, a second medication is added, with options including SGLT-2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, or thiazolidinediones. For patients still not meeting targets, insulin therapy is typically introduced, often starting with basal insulin. The choice between second-line agents depends on patient-specific factors, and SGLT-2 inhibitors and GLP-1 receptor agonists are often preferred for patients with established cardiovascular disease or high risk factors due to their proven cardiovascular benefits, as supported by the 2019 guidelines 1. These medications work through different mechanisms, including reducing hepatic glucose production, increasing urinary glucose excretion, enhancing insulin secretion, and reducing glucagon, while insulin directly lowers blood glucose by facilitating cellular uptake. It's essential to consider the individualized glycemic and weight goals as well as the presence of other metabolic comorbidities and the risk of hypoglycemia when selecting subsequent glucose-lowering agents, as recommended in the 2021 guidelines 1. Additionally, a person-centered shared decision-making approach should guide the choice of pharmacologic agents, taking into account the effects on cardiovascular and renal comorbidities, effectiveness, hypoglycemia risk, impact on weight, cost, and access, risk for adverse reactions and tolerability, and individual preferences, as emphasized in the 2016 guidelines 1 and the 2018 World Health Organization guidelines 1.

From the FDA Drug Label

The stepwise medication treatments for type 2 diabetes are not explicitly outlined in the provided drug labels. However, the labels do provide information on the efficacy and safety of specific medications, such as empagliflozin and liraglutide, as add-on therapies to metformin and other medications.

The medications mentioned in the labels include:

• Metformin: often used as a first-line treatment for type 2 diabetes
• Empagliflozin: an SGLT2 inhibitor that can be used as an add-on therapy to metformin
• Liraglutide: a GLP-1 receptor agonist that can be used as an add-on therapy to metformin and other medications
• Sulfonylurea: a class of medications that can be used in combination with metformin
• Linagliptin: a DPP-4 inhibitor that can be used in combination with metformin
• Rosiglitazone: a thiazolidinedione that can be used in combination with metformin

A possible stepwise approach to medication treatment for type 2 diabetes could be:

• Step 1: Metformin monotherapy
• Step 2: Add a second medication, such as a sulfonylurea, SGLT2 inhibitor (e.g. empagliflozin), or DPP-4 inhibitor (e.g. linagliptin)
• Step 3: Add a third medication, such as a GLP-1 receptor agonist (e.g. liraglutide) or a thiazolidinedione (e.g. rosiglitazone)

However, it is essential to note that the specific stepwise approach may vary depending on individual patient factors, such as renal function, cardiovascular risk, and medication tolerability. Therefore, the treatment plan should be tailored to each patient's needs, and medication adjustments should be made under the guidance of a healthcare professional 2, 3.

From the Research

Stepwise Medication Treatments for Type 2 Diabetes

The treatment of type 2 diabetes typically involves a stepwise approach, with the initial treatment often being metformin due to its favorable profile, including glucose-lowering ability, weight-neutral effects, and low risk of hypoglycemia 4.

Initial Treatment

• Metformin is considered the first-line treatment for type 2 diabetes by leading recommendations 5, 6, 4.
• It works by enhancing insulin sensitivity, inducing greater peripheral uptake of glucose, and decreasing hepatic glucose output 4.
• Extended-release metformin is available for patients who experience gastrointestinal intolerance with the immediate-release formulation, offering improved tolerability and the convenience of once-daily dosing 7.

Alternative and Combination Therapies

• When metformin is contraindicated or not tolerated, other classes of agents can be used, including sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) 5, 6.
• Combination therapy, such as pairing an SGLT2 inhibitor with a dipeptidyl peptidase-4 inhibitor (DPP-4I), can be an effective strategy for managing type 2 diabetes, offering complementary modes of action and enhanced glucose-lowering effects without significantly increasing the risk of hypoglycemia 8.
• The choice of medication or combination thereof should consider factors such as overall efficacy in A1c reduction, adverse effect profile, cost, and patient preference 5.

Stepwise Approach

• The stepwise approach may involve starting with metformin and then adding other medications as needed to achieve glycemic control 5, 8.
• The addition of medications should be based on the patient's response to initial therapy, tolerability, and the presence of any comorbid conditions or contraindications to specific therapies 6, 8.