What medication to add to metformin (biguanide) for a patient with an HbA1c (hemoglobin A1c) level of 10.5%?

From the Guidelines

For a patient with an HbA1c of 10.5% who is already on metformin 2000 mg, I recommend adding a GLP-1 receptor agonist such as semaglutide (Ozempic) or dulaglutide (Trulicity) as the preferred second agent, as supported by the most recent guidelines 1. This approach is based on the patient's significantly elevated HbA1c level, indicating severe hyperglycemia that requires intensification of treatment. The choice of a GLP-1 receptor agonist is due to its potent A1c-lowering effect (1-1.5%), weight loss benefits, low hypoglycemia risk, and cardiovascular protection, as highlighted in recent studies 1. Alternatively, insulin therapy (particularly basal insulin like insulin glargine) or SGLT-2 inhibitors like empagliflozin could be considered, especially if the patient has cardiovascular or kidney disease, as suggested by recent guidelines 1. Key considerations in selecting the second agent include the patient's clinical characteristics, comorbidities, cost, and preferences regarding injection therapy versus oral medication, as emphasized in the standards of medical care in diabetes 1. The initial dose of semaglutide could be 0.25 mg subcutaneously weekly for 4 weeks, then increased to 0.5 mg weekly, with potential further titration to 1 mg weekly if needed, based on the patient's response and tolerance. Ultimately, the decision should be individualized and made through a shared decision-making process with the patient, taking into account the latest evidence and guidelines 1. It is crucial to monitor the patient's response to the new treatment regimen and adjust as necessary to achieve and maintain glycemic targets, as recommended by recent consensus reports 1. In patients with established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, an SGLT2 inhibitor or GLP-1 RA with demonstrated CVD benefit is recommended as part of the glucose-lowering regimen, independent of A1C or metformin use, as suggested by recent guidelines 1. The goal is to improve glycemic control, reduce the risk of complications, and enhance the patient's quality of life, while minimizing potential side effects and considering cost and patient preferences, as emphasized in recent studies 1.

From the FDA Drug Label

In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to VICTOZA 0.6 mg, VICTOZA 1.2 mg, VICTOZA 1. 8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Treatment with VICTOZA 1. 2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA1c reduction relative to glimepiride 4 mg add-on to metformin (Table 4).

Liraglutide (VICTOZA) can be considered as an add-on medication to metformin for a patient with an HbA1c level of 10.5%.

• The starting dose of liraglutide is 0.6 mg/day, and the dose can be increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg.
• The patient is already on metformin 2000 mg, which is the maximum dose.
• Liraglutide has been shown to result in a significant mean HbA1c reduction when used as an add-on to metformin 2.

From the Research

Medication Options to Add to Metformin

For a patient with an HbA1c level of 10.5% who is already taking metformin 2000mg, several medication options can be considered to add to their current regimen.

• GLP-1 Receptor Agonists: Studies such as 3 and 4 suggest that GLP-1 receptor agonists (e.g., exenatide, liraglutide, dulaglutide) can be effective in reducing HbA1c levels. These medications have been shown to provide significant HbA1c reductions, especially in patients with higher baseline HbA1c levels.
• SGLT2 Inhibitors: Research like 5 and 6 indicates that SGLT2 inhibitors (e.g., empagliflozin, canagliflozin) can also be beneficial in lowering HbA1c levels and may offer additional benefits such as weight loss and cardiovascular protection.
• DPP-4 Inhibitors: Although 7 suggests that DPP-4 inhibitors may not be as effective as GLP-1 receptor agonists or SGLT2 inhibitors in reducing HbA1c, they can still be considered as an add-on therapy, especially if other options are not suitable.

Considerations for Choosing an Add-on Medication

When selecting an add-on medication to metformin, factors such as the patient's current HbA1c level, presence of comorbidities (e.g., cardiovascular disease, kidney disease), potential side effects, and the patient's ability to administer the medication (e.g., injections vs. oral medications) should be taken into account.

• Combination Therapy: 6 discusses the potential benefits of combining GLP-1 receptor agonists with SGLT2 inhibitors, suggesting that this combination may offer additive benefits in terms of glycemic control and cardiovascular protection. However, the decision to use combination therapy should be individualized based on the patient's specific needs and response to treatment.