What is a suitable adjunct medication to metformin (Metformin) for a patient with hyperglycemia (elevated Hemoglobin A1c)?

From the Guidelines

For patients with high A1c not adequately controlled on metformin alone, a GLP-1 receptor agonist is the most recommended addition, as it offers significant A1c reduction and cardiovascular benefits, as suggested by the most recent guidelines 1. When considering adding a medication to metformin for a patient with a high A1c, several factors such as cardiovascular risk, kidney function, and weight concerns should be taken into account.

• The American Diabetes Association recommends considering dual-combination therapy or a more potent glucose-lowering agent when A1C is ≥1.5% above the individualized glycemic goal 1.
• GLP-1 receptor agonists, such as semaglutide, have been shown to be effective in reducing A1c levels (1-1.8% decrease) and promoting weight loss, while also offering cardiovascular benefits 1.
• SGLT-2 inhibitors, such as empagliflozin, provide moderate A1c reduction (0.5-0.7%) with heart failure and kidney disease benefits, making them a suitable alternative for patients with established cardiovascular disease 1.
• Sulfonylureas, like glipizide, are effective but carry a higher risk of hypoglycemia and potential weight gain, making them a less preferred option 1. Regular monitoring of kidney function and patient education on potential side effects are necessary when starting these medications.
• The choice of medication should be individualized based on the patient's specific needs and circumstances, taking into account factors such as insurance coverage and potential side effects 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) is a good medication to add to metformin for a patient with a high A1c, as it has been shown to provide statistically significant reductions in HbA1c when used in combination with metformin.

• The recommended dose is 1.2 mg or 1.8 mg once daily, with a starting dose of 0.6 mg to reduce gastrointestinal intolerance.
• The addition of liraglutide to metformin has been shown to result in significant improvements in HbA1c and fasting plasma glucose (FPG) compared to placebo.
• Liraglutide has also been compared to sitagliptin, another medication used to treat type 2 diabetes, and has been shown to result in statistically significant reductions in HbA1c relative to sitagliptin.
• Another option is empagliflozin (JARDIANCE), which has also been shown to provide statistically significant reductions in HbA1c when used in combination with metformin.
• The recommended dose of empagliflozin is 10 mg or 25 mg once daily.
• Empagliflozin has been shown to result in significant improvements in HbA1c, FPG, and body weight compared to placebo when used in combination with metformin 2 3.

From the Research

Medication Options to Add to Metformin

For a patient with a high A1c, several medication options can be considered to add to metformin. These include:

• GLP-1 Receptor Agonists (GLP-1 RAs)
• Sodium-Glucose Cotransporter 2 Inhibitors (SGLT-2i)
• Dipeptidyl Peptidase-4 Inhibitors (DPP-4i)

Efficacy of Medications

Studies have shown that:

• The combination of GLP-1 RA, SGLT-2i, and DPP-4i can significantly reduce HbA1c levels 4
• GLP-1 RAs, such as exenatide, liraglutide, and dulaglutide, have been shown to have greater reductions in FPG and HbA1c compared to other medications 5
• SGLT-2i have been shown to cause a more robust A1c reduction and more weight loss compared to DPP-4i, but with more genital infections 6

Combination Therapy

Combination therapy with metformin and other medications has been shown to be effective:

• The combination of GLP-1 RAs and SGLT-2i has been shown to be safe and effective in reducing MACE outcomes 7
• The combination of SGLT-2i and GLP-1 agonists may have promising nephroprotective outcomes, but more research is needed to fully understand their effects on microvascular complications 8

Key Findings

Key findings from the studies include:

• GLP-1 RAs can significantly reduce body weight and basic insulin dosage 4
• SGLT-2i can cause significant weight loss and reduce A1c levels, but may increase the risk of genital infections 6
• DPP-4i have a lower risk of hypoglycemia compared to GLP-1 RAs 4