From the Guidelines
For a patient with an HbA1c greater than 14% who is already on a maximum dose of metformin, the recommended next step is to initiate a GLP-1 receptor agonist, such as liraglutide (Victoza) or semaglutide (Ozempic), starting at the lowest dose and titrating up as tolerated, as this may be sufficient for achieving individualized A1C goals with lower risk of hypoglycemia and favorable weight, cardiovascular, kidney, and liver profiles 1. When considering the management of a patient with severe hyperglycemia, several factors must be taken into account, including the potential for hypoglycemia, weight gain, and cardiovascular risk.
- The patient's current regimen of maximum dose metformin indicates a need for additional therapy to achieve glycemic control.
- The introduction of a GLP-1 receptor agonist can provide significant glucose-lowering effects, with studies suggesting a 1 to 2% lowering of A1C when added to metformin 1.
- If the patient's glycemic goals are not met with the addition of a GLP-1 receptor agonist, basal insulin, such as insulin glargine (Lantus) or insulin detemir (Levemir), can be initiated at an initial dose of 0.1-0.2 units/kg/day, typically given once daily, to provide rapid and potent glucose-lowering effects. Key considerations in the choice of antidiabetic agent include:
- Efficacy in lowering blood glucose
- Risk of hypoglycemia
- Impact on weight
- Cardiovascular risk reduction
- Patient preferences and comorbidities Given the most recent evidence from 2025, the approach to pharmacologic treatment of type 2 diabetes emphasizes a patient-centered approach, considering multiple individualized treatment goals simultaneously, including glycemic control, weight management, and cardiovascular risk reduction 1.
From the Research
Antidiabetic Agents for Severe Hyperglycemia
In patients with severe hyperglycemia (HbA1c > 14) who are on a maximum dose of Metformin, several antidiabetic agents can be considered as add-on therapy.
- Sulphonylureas: These drugs can lower HbA1c levels by an average of 0.8% to 1% when added to metformin, but they can cause dose-related hypoglycaemia 2.
- Human Insulins: A daily injection of long-acting insulin can lower HbA1c by 0.7% to 2.5% on average, but it can cause weight gain and increase the risk of hypoglycaemia 2.
- GLP-1 Receptor Agonists: These agents, such as exenatide and liraglutide, have a glucose-lowering potency similar to one or two daily insulin injections and can induce weight loss without increasing the risk of hypoglycaemia 2, 3.
- SGLT2 Inhibitors: Empagliflozin, a SGLT2 inhibitor, has been shown to reduce HbA1c levels by 0.59% to 0.69% when added to pioglitazone with or without metformin 4, 5.
Considerations for Choosing an Antidiabetic Agent
When choosing an antidiabetic agent, several factors should be considered, including the patient's renal function, risk of hypoglycaemia, and potential for weight gain or loss.
- Renal Function: Metformin is contraindicated in patients with severe renal impairment, and the use of other antidiabetic agents may need to be adjusted based on renal function 6.
- Hypoglycaemia Risk: Sulphonylureas and human insulins can increase the risk of hypoglycaemia, while GLP-1 receptor agonists and SGLT2 inhibitors may have a lower risk of hypoglycaemia 2, 3.
- Weight Gain or Loss: Human insulins can cause weight gain, while GLP-1 receptor agonists and SGLT2 inhibitors may promote weight loss 2, 3, 4, 5.