What is the next line of treatment for a patient on metformin (biguanide) with uncontrolled blood sugar levels?

From the Guidelines

For a patient on metformin with uncontrolled blood sugar levels, the next line of treatment should involve adding an SGLT-2 inhibitor or a GLP-1 agonist to metformin and lifestyle modifications, as recommended by the American College of Physicians 1. This approach is based on high-certainty evidence and takes into account the patient's clinical characteristics, comorbidities, and preferences. When considering the addition of a second agent, it is essential to ensure the patient is taking the maximum tolerated dose of metformin (typically 2000mg daily) and has addressed lifestyle factors like diet and exercise. The choice of second agent should be individualized, considering factors such as:

• Comorbidities, including cardiovascular disease or kidney disease
• Risk of hypoglycemia
• Weight considerations
• Cost
• Patient preferences Combination therapy works through complementary mechanisms, with metformin reducing hepatic glucose production and improving insulin sensitivity, and the second agent targeting different aspects of glucose regulation, such as:
• Increasing insulin secretion
• Reducing glucose reabsorption in the kidneys
• Slowing gastric emptying According to the American Diabetes Association standards of medical care in diabetes, combination therapy should be considered when monotherapy with a noninsulin agent at the maximum tolerated dose does not achieve or maintain the HbA1c target over 3 months 1. Additionally, the 2020 standards of medical care in diabetes suggest that initial combination therapy may be beneficial for more rapid attainment of glycemic goals, especially in patients presenting with A1C levels 1.5–2.0% above target 1. However, the most recent and highest quality study recommends adding an SGLT-2 inhibitor or a GLP-1 agonist to metformin and lifestyle modifications 1.

From the FDA Drug Label

The mean daily dose of glimepiride was 2. 7 mg and the maximal approved dose in the United States is 8 mg per day. Table 8 Results at Week 52 from an Active-Controlled Study Comparing JARDIANCE to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin JARDIANCE 25 mg + MetforminN=765Glimepiride + MetforminN=780 HbA1c (%)a Baseline (mean)7.97.9 Change from baseline (adjusted mean)-0.7-0.7 Difference from glimepiride (adjusted mean) (97.5% CI)-0.07b (-0.15,0. 01)--

The next line of treatment for a patient on metformin with uncontrolled blood sugar levels could be the addition of other medications such as JARDIANCE (empagliflozin) or glimepiride.

• Key points:
  • JARDIANCE can be used as add-on therapy to metformin.
  • Glimepiride can also be used as add-on therapy to metformin.
  • The choice of next line of treatment should be based on individual patient factors and clinical judgment. 2

From the Research

Next Line of Treatment for Uncontrolled Blood Sugar on Metformin

• If a patient's blood sugar is not controlled while on metformin, the next line of treatment may involve adding another medication to the existing metformin regimen 3.
• According to recent studies, newer agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists may be favored as add-on therapies due to their significant positive effects on glycemia and added benefits in patients with obesity, renal disease, heart failure, and cardiovascular disease 3, 4.
• A study published in 2024 investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus, and found that this combination led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria 5.
• Another study published in 2012 conducted a systematic review and meta-analysis to evaluate the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled with metformin and sulphonylurea combination therapy, and found that insulins, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogues, and thiazolidinediones all produced statistically significant reductions in hemoglobin A1c in combination with metformin and a sulphonylurea 6.
• The choice of next-line treatment should be individualized based on patient factors, such as presence of cardiovascular or renal disease, and should take into account the potential benefits and risks of each medication, including effects on weight, hypoglycemia, and other adverse events 6, 4.