From the Guidelines
For patients with type 2 diabetes who need additional medication after metformin and do not have chronic kidney disease (CKD), a GLP-1 receptor agonist or an SGLT-2 inhibitor is generally the preferred next option, as they offer excellent glycemic control with added benefits of weight loss, cardiovascular protection, and reduced risk of kidney disease progression, as supported by the most recent guidelines 1. When considering the next step after metformin, it's crucial to weigh the benefits and risks of each medication class. GLP-1 receptor agonists, such as semaglutide, dulaglutide, or liraglutide, are preferred for their ability to provide glycemic control, promote weight loss, and offer cardiovascular protection, as evidenced by recent studies 1. SGLT-2 inhibitors, like empagliflozin, dapagliflozin, or canagliflozin, are also excellent choices due to their cardiovascular benefits, modest weight loss, and some blood pressure reduction, as noted in the 2021 guideline 1. Key considerations for choosing between these options include:
- Cardiovascular risk: Both GLP-1 agonists and SGLT-2 inhibitors have proven cardiovascular outcome benefits, making them ideal for patients with established atherosclerotic cardiovascular disease, as highlighted in the 2021 guideline 1.
- Weight concerns: GLP-1 agonists tend to promote more significant weight loss compared to SGLT-2 inhibitors.
- Hypoglycemia risk: GLP-1 agonists and SGLT-2 inhibitors have a lower risk of hypoglycemia compared to sulfonylureas.
- Cost considerations and medication preferences: These factors should be individualized based on the patient's specific needs and circumstances. In cases where these medications are not tolerated or are insufficient, alternatives such as DPP-4 inhibitors, sulfonylureas, or thiazolidinediones may be considered, taking into account their respective benefits and risks, as discussed in the 2016 American Diabetes Association standards of medical care in diabetes 1.
From the Research
Medication Options After Metformin
When metformin is not sufficient to control blood sugar levels in patients with type 2 diabetes, several medication options can be considered as add-on therapies. These include:
- Dipeptidyl peptidase 4 inhibitors (DPP-4i) 2
- Sulphonylureas (SU) 2
- Thiazolidinediones (TZD) 2
- Sodium glucose co-transporter 2 inhibitors (SGLT2i) 2, 3
- Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) 4, 5
Efficacy of Medications
Studies have shown that these medications can be effective in lowering HbA1c levels, with similar percentages of patients achieving the recommended HbA1c target of <7.5% (58 mmol/mol) at 6 and 12 months 2. The choice of medication may depend on individual patient characteristics, such as age and clinical characteristics 2.
Safety and Cardiovascular Outcomes
The safety and cardiovascular outcomes of these medications have also been studied. SGLT-2 inhibitors have been shown to have beneficial effects on mortality, major cardiovascular adverse events, and hospitalization for heart failure, particularly in patients with established cardiovascular disease or kidney disease 3, 5. GLP-1 RAs have also been shown to have beneficial effects on mortality and major cardiovascular adverse events, although the absolute effects may be limited in patients with low cardiovascular risk 5.
Treatment Intensification
Treatment intensification with add-on therapies is often necessary when patients fail to achieve glycemic control with metformin monotherapy. The distance to glycemic goal at the time of treatment intensification can vary, with a mean distance to goal of 1.7% (median 1.2%) in patients who received intensified treatment 6.
Patient Characteristics and Treatment Response
Patient characteristics, such as age and clinical characteristics, may influence individual treatment response. For example, SGLT2i and SUs may be more effective in relatively younger and older people, respectively 2. Accounting for these characteristics in clinical treatment decisions may facilitate individualized prescribing and improve treatment outcomes.