What is the role of sulfonylureas (SUs) in the management of long-standing type 2 diabetes mellitus (T2DM)?

Role of Sulfonylureas in Long-Standing Type 2 Diabetes Mellitus

Sulfonylureas should not be first-line therapy for patients with long-standing type 2 diabetes mellitus (T2DM), especially in those with established cardiovascular disease, due to their association with hypoglycemia, weight gain, and lack of durable glycemic control. 1

Mechanism of Action and Efficacy

• Sulfonylureas lower glucose by stimulating insulin secretion from pancreatic β-cells, requiring functioning β-cells to be effective 2
• They have high glucose-lowering efficacy and were used in landmark studies like UKPDS and ADVANCE, which demonstrated reductions in microvascular complications 1
• Sulfonylureas are inexpensive, widely available, and have favorable cost profiles compared to newer agents 1
• They are known to lack durable effect on glucose lowering over time, which is particularly problematic in long-standing diabetes where β-cell function is already compromised 1

Safety Considerations in Long-Standing Diabetes

Hypoglycemia Risk

• Sulfonylureas are associated with an increased risk of hypoglycemia, which is particularly concerning in patients with long-standing diabetes 1
• Hypoglycemia can cause direct harm including falls, injuries, fractures, motor vehicle accidents, and potentially fatal cardiac arrhythmias 1
• The risk of hypoglycemia varies among different sulfonylureas:
  • Newer-generation agents like glipizide, glimepiride, and gliclazide may have a lower risk of hypoglycemia compared to older agents 1
  • Patient education and use of low or variable dosing can help mitigate hypoglycemia risk 1

Cardiovascular Considerations

• Concerns have been raised about potential adverse cardiovascular outcomes with sulfonylureas in observational studies 1
• Recent systematic reviews have found no increase in all-cause mortality compared with other active treatments 1
• The CAROLINA trial showed no difference in cardiovascular outcomes between glimepiride and linagliptin (a DPP-4 inhibitor), though sulfonylureas had higher hypoglycemia rates 1
• In patients with established coronary artery disease (CAD), sulfonylureas should not be first-line therapy due to concerns about hypoglycemia and potential effects on cardiac ischemic preconditioning 1

Weight Effects

• Sulfonylureas are associated with weight gain, though this is relatively modest in large cohort studies 1
• This weight gain may be detrimental in long-standing diabetes where obesity is often a comorbidity 1

Patient Selection for Sulfonylurea Therapy

Appropriate Candidates

• Patients for whom cost is a significant barrier to medication adherence 1
• Patients with preserved β-cell function (typically earlier in the disease course) 1
• Patients without high risk for hypoglycemia 1

Patients Requiring Caution

• Elderly patients or those with chronic kidney disease due to increased hypoglycemia risk 1
• Patients with established cardiovascular disease 1
• Patients with very long-standing diabetes who may have significant β-cell dysfunction 1

Practical Considerations for Use in Long-Standing Diabetes

• When using sulfonylureas in long-standing diabetes:
  • Choose newer-generation agents (glimepiride, gliclazide, glipizide) with lower hypoglycemia risk 1
  • Consider lower starting doses (e.g., glimepiride 1 mg daily) 3
  • Administer approximately 30 minutes before meals to achieve the greatest reduction in postprandial hyperglycemia 2
  • Monitor for hypoglycemia, especially in high-risk patients 1
  • Be aware of potential drug interactions that may increase hypoglycemia risk 2

Position in Current Treatment Algorithms

• Current guidelines from the ADA/EASD (2022) no longer position sulfonylureas as preferred second-line agents after metformin 1
• For patients with established cardiovascular disease, SGLT-2 inhibitors or GLP-1 receptor agonists are preferred due to their cardiovascular benefits 1
• In patients with heart failure, sulfonylureas may be used cautiously but are not preferred agents 1
• When cost is a major consideration, sulfonylureas remain a reasonable option due to their low cost and efficacy 1

Conclusion

In long-standing T2DM, sulfonylureas have limited utility due to their mechanism requiring functioning β-cells, risk of hypoglycemia, weight gain, and lack of cardiovascular benefits. They should be considered primarily when cost is a major barrier to treatment, when newer agents are contraindicated, or in specific patients with preserved β-cell function. When used, newer-generation agents at lower doses with careful monitoring are preferred to minimize adverse effects.