What is the next step if metformin (biguanide) alone is insufficient to control hyperglycemia?

From the Guidelines

If metformin alone is insufficient to control hyperglycemia, the next step typically involves adding a second antihyperglycemic agent, such as an SGLT-2 inhibitor or a GLP-1 agonist, to metformin and lifestyle modifications. The choice of second-line medication depends on patient-specific factors including:

• Cardiovascular risk
• Renal function
• Hypoglycemia risk
• Cost considerations
• Patient preferences Common second-line options include:
• Sodium-glucose cotransporter-2 (SGLT2) inhibitors (such as empagliflozin, dapagliflozin, or canagliflozin)
• Glucagon-like peptide-1 (GLP-1) receptor agonists (such as semaglutide, dulaglutide, or liraglutide)
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (such as sitagliptin or linagliptin)
• Sulfonylureas (such as glipizide or glimepiride)
• Thiazolidinediones (such as pioglitazone)
• Basal insulin (such as insulin glargine or detemir) For patients with established cardiovascular disease or high cardiovascular risk, SGLT2 inhibitors or GLP-1 receptor agonists are often preferred due to their demonstrated cardiovascular benefits, as recommended by the American College of Physicians 1. The medication should be started at the recommended initial dose and titrated as needed based on blood glucose monitoring results. This dual therapy approach works by targeting different pathophysiological mechanisms of hyperglycemia, providing complementary effects to metformin's action of decreasing hepatic glucose production and improving insulin sensitivity. According to the American Diabetes Association, metformin is the preferred initial pharmacologic agent, and when monotherapy with metformin does not achieve or maintain the HbA1c target, a second agent should be added 1.

From the FDA Drug Label

Add-On Combination Therapy with Metformin and Sulfonylurea A total of 666 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin plus a sulfonylurea Patients with inadequately controlled type 2 diabetes on at least 1500 mg per day of metformin and on a sulfonylurea, entered a 2 week open-label placebo run-in. In Combination with Linagliptin as Add-On to Metformin Therapy A total of 686 patients with type 2 diabetes participated in a double-blind, active-controlled study to evaluate the efficacy and safety of JARDIANCE 10 mg or 25 mg in combination with linagliptin 5 mg compared to the individual components Active-Controlled Study versus Glimepiride in Combination with Metformin The efficacy of JARDIANCE was evaluated in a double-blind, glimepiride-controlled, study in 1545 patients with type 2 diabetes with insufficient glycemic control despite metformin therapy

The next step if metformin alone is insufficient to control hyperglycemia is to add another medication, such as:

• Sulfonylurea: adding a sulfonylurea to metformin can provide statistically significant reductions in HbA1c, FPG, and body weight.
• Linagliptin: adding linagliptin to metformin can provide statistically significant improvement in HbA1c and FPG.
• Empagliflozin (JARDIANCE): adding empagliflozin to metformin can provide statistically significant reductions in HbA1c, FPG, and body weight.
• Glimepiride: adding glimepiride to metformin can lower HbA1c and FPG. 2

From the Research

Next Steps After Metformin

If a patient is unable to control their blood glucose level with metformin, several options can be considered as the next step:

• Adding another oral antidiabetic drug, such as a sulfonylurea or a thiazolidinedione, to the treatment regimen 3
• Using a GLP-1 receptor agonist or a DPP-4 inhibitor as an add-on therapy to metformin 4, 5
• Initiating basal insulin therapy, with or without additional short-acting premeal doses 5, 6
• Considering the use of newer agents, such as sodium-glucose cotransporter-2 inhibitors, which have been shown to have significant positive effects on glycemia and added benefits in patients with obesity, renal disease, heart failure, and cardiovascular disease 7

Considerations for Therapy Selection

When selecting the next step in therapy, several factors should be taken into account:

• The patient's individual characteristics, such as renal function, cardiovascular risk, and presence of other comorbidities 3, 7
• The potential risks and benefits of each therapy option, including the risk of hypoglycemia, weight gain, and other adverse effects 3, 5
• The patient's previous experience with diabetes medications and their ability to adhere to the prescribed treatment regimen 6

Monitoring and Follow-Up

Regardless of the chosen therapy, regular monitoring of blood glucose levels, kidney function, and other relevant parameters is essential to ensure the patient's safety and adjust the treatment plan as needed 3, 6