What is a reasonable third oral antidiabetic medication to add to a regimen for a patient with hyperglycemia (elevated blood glucose), already taking metformin and dapagliflozin, who refuses insulin therapy and has a hemoglobin A1c (HbA1c) level indicating poor glucose control?

From the Guidelines

For a patient with hyperglycemia already taking metformin and dapagliflozin, who refuses insulin therapy, a reasonable third oral antidiabetic medication to add would be a GLP-1 receptor agonist like semaglutide (Rybelsus) or a DPP-4 inhibitor such as sitagliptin (Januvia). This recommendation is based on the most recent evidence from 1, which provides a comprehensive overview of pharmacologic approaches to glycemic treatment. Given the patient's poor glucose control, as indicated by their hemoglobin A1c (HbA1c) level, the addition of a GLP-1 receptor agonist or a DPP-4 inhibitor can help achieve better glycemic control without the need for insulin therapy. Semaglutide, in particular, has been shown to be effective in reducing HbA1c levels and has the advantage of not causing hypoglycemia when used without insulin or sulfonylureas 1. The patient should be monitored for potential side effects such as nausea, vomiting, and diarrhea, which typically improve over time. If GLP-1 therapy is not suitable, a sulfonylurea like glimepiride could be considered, although it carries a higher hypoglycemia risk. It is essential to inform the patient that if oral therapy fails to achieve adequate control, insulin may become necessary despite their preferences. Additionally, consideration of the patient's kidney function is crucial, as some medications may require dose adjustments or are contraindicated in certain stages of chronic kidney disease, as outlined in 1. However, for the purpose of this recommendation, the focus remains on the most effective and recent evidence supporting the use of GLP-1 receptor agonists or DPP-4 inhibitors as a third-line treatment for hyperglycemia. Key points to consider include:

• The patient's significantly elevated HbA1c level, indicating poor glucose control
• The need to avoid insulin therapy due to patient refusal
• The effectiveness of GLP-1 receptor agonists, such as semaglutide, in reducing HbA1c levels without causing hypoglycemia
• The potential side effects of GLP-1 therapy and the importance of monitoring
• The consideration of alternative options, such as sulfonylureas, if GLP-1 therapy is not suitable
• The importance of considering the patient's kidney function when selecting a medication.

From the FDA Drug Label

Add-On Combination Therapy with a Sulfonylurea A total of 597 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with glimepiride (a sulfonylurea) In combination with glimepiride, dapagliflozin 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24

A reasonable third oral antidiabetic medication to add to a regimen for a patient with hyperglycemia, already taking metformin and dapagliflozin, who refuses insulin therapy and has a hemoglobin A1c (HbA1c) level indicating poor glucose control is a sulfonylurea, such as glipizide or glimepiride 2.

• Key benefits of adding a sulfonylurea include:
  • Improvement in HbA1c
  • Reduction in body weight
  • Improvement in FPG and 2-hour PPG
• Important consideration: down-titration of the sulfonylurea may be necessary to prevent hypoglycemia.

From the Research

Reasonable Third Oral Antidiabetic Medication

To determine a reasonable third oral antidiabetic medication for a patient with hyperglycemia already taking metformin and dapagliflozin, and who refuses insulin therapy, several options can be considered based on existing studies 3, 4, 5, 6, 7.

• Pioglitazone as an Option: A study published in 2024 4 found that the addition of pioglitazone to metformin and dapagliflozin resulted in significant reductions in HbA1c levels, indicating improved glycemic control. The study showed that pioglitazone, at both 15 mg and 30 mg daily doses, was effective and had a favorable safety profile when added to the regimen of patients with type 2 diabetes inadequately controlled with metformin and dapagliflozin.
• Combination Therapies: Another study from 2022 5 compared the efficacy of glimepiride, alogliptin, and alogliptin-pioglitazone in patients with poorly controlled type 2 diabetes mellitus. It found that the combination of alogliptin and pioglitazone showed significant reductions in HbA1c levels and improvements in glycemic variability compared to alogliptin alone or glimepiride.
• Dapagliflozin's Role: The use of dapagliflozin, an SGLT2 inhibitor, in combination with other antidiabetic drugs, including metformin and pioglitazone, has been shown to provide complementary therapy via its unique mechanism of action, reducing renal glucose reabsorption and leading to urinary glucose excretion 6.
• Triple Oral Fixed-Dose Combination: A study from 2011 7 demonstrated the efficacy of a fixed-dose triple oral diabetes polypill containing glimepiride, metformin, and pioglitazone compared to insulin plus metformin in insulin-naive subjects with type 2 diabetes mellitus inadequately controlled on a combination of glimepiride and metformin. The triple oral fixed-dose combination showed a trend towards lower HbA1c levels and was associated with better efficacy and tolerability assessments.

Considerations for Selection

When selecting a third oral antidiabetic medication, considerations should include the patient's current regimen, the mechanism of action of the potential new medication, efficacy, safety profile, and patient-specific factors such as renal function, risk of hypoglycemia, and potential for weight gain or loss 3, 4, 5, 6, 7.

• Efficacy and Safety: The chosen medication should demonstrate significant efficacy in improving glycemic control, as measured by HbA1c levels, and have a favorable safety profile with minimal risk of adverse events.
• Patient Preferences: Patient refusal of insulin therapy indicates a preference for oral medications, making the selection of an effective and safe oral agent crucial.
• Combination Therapy: The potential benefits of combination therapy, including improved glycemic control and reduced risk of hypoglycemia, should be considered when selecting a third oral antidiabetic medication.