What is the role of sulfonureas (sulfonylureas) in the treatment of type 2 diabetes?

Role of Sulfonylureas in Type 2 Diabetes Treatment

Sulfonylureas should be used as second-line therapy when metformin alone fails to achieve glycemic control or when metformin is contraindicated, but they are now considered inferior to SGLT-2 inhibitors and GLP-1 agonists for most patients due to increased risks of hypoglycemia, mortality, and cardiovascular events. 1

Current Position in Treatment Algorithm

Second-Line Therapy (Traditional Approach)

• The WHO strongly recommends adding a sulfonylurea to patients with type 2 diabetes who do not achieve glycemic control with metformin alone or who have contraindications to metformin 1
• Sulfonylureas lower HbA1c by approximately 1.5 percentage points, similar to metformin's efficacy 1
• They work by enhancing insulin secretion from pancreatic beta cells through stimulation of the sulfonylurea receptor 2

Evolving Evidence Against First-Line Use

• The American College of Physicians now recommends prioritizing SGLT-2 inhibitors or GLP-1 agonists over sulfonylureas as add-on therapy to metformin 1
• When SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, clinicians should reduce or discontinue sulfonylureas due to increased risk for severe hypoglycemia 1
• Sulfonylureas and long-acting insulins are explicitly stated as inferior to SGLT-2 inhibitors and GLP-1 agonists in reducing all-cause mortality and morbidity 1

Safety Profile and Key Risks

Hypoglycemia Risk

• Severe hypoglycemia requiring assistance, causing coma, or seizure is the major adverse effect, though such episodes are infrequent 1
• Risk is substantially higher with first-generation agents (chlorpropamide) and glyburide compared to second-generation sulfonylureas (gliclazide, glimepiride, glipizide) 1
• Prefer second-generation sulfonylureas if using this class 1
• DPP-4 inhibitors have 86% lower odds of severe hypoglycemia (OR 0.14) and SGLT-2 inhibitors have 91% lower odds (OR 0.09) compared to sulfonylureas 1

Mortality and Cardiovascular Concerns

• Real-world evidence shows sulfonylureas as first-line therapy (versus metformin) increase ischemic stroke by 25% (HR 1.25), cardiovascular death by 25% (HR 1.25), and all-cause mortality by 60% (HR 1.60) 3
• As add-on therapy to metformin, sulfonylureas increase all-cause mortality by 44% (HR 1.44) and major hypoglycemic episodes by 178% (HR 2.78) compared to other oral agents 4
• No significant difference in cardiovascular mortality was found in high-risk CVD patients in WHO analysis, though evidence quality was very low 1

Weight Gain

• Weight gain of approximately 2 kg is common following sulfonylurea initiation 1
• This contrasts with SGLT-2 inhibitors and GLP-1 agonists, which promote weight loss 1

When Sulfonylureas Remain Appropriate

Resource-Limited Settings

• In low-resource settings, sulfonylureas remain the preferred second-line option due to cost considerations 1
• Newer agents (DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists) cost several times more than sulfonylureas or human insulin 1

Specific Clinical Scenarios

• Sulfonylureas are the preferred treatment for certain types of monogenic diabetes 5
• They remain commonly used in patients with heart failure, where approximately half of Medicare recipients with HF are treated with sulfonylureas, and observational data shows no increased mortality in this population 1
• When insulin is unsuitable (e.g., patients living alone who depend on others for injections), sulfonylureas may be used as third-line therapy before considering newer agents 1

Glycemic Efficacy

• Sulfonylureas demonstrate comparable HbA1c reduction to DPP-4 inhibitors and TZDs, with DPP-4 inhibitors actually showing slightly worse glycemic control (0.12% higher HbA1c versus sulfonylureas) 1
• Durability of glycemic control appears comparable to newer agents 5

Practical Prescribing Considerations

Agent Selection Within Class

• Choose second-generation sulfonylureas (gliclazide, glimepiride, glipizide) over first-generation agents or glyburide 1
• Glimepiride may preserve cardioprotective responses to ischemia better than other sulfonylureas due to differential binding affinity 6
• Newer-generation sulfonylureas do not appear to impair cardiac ischemic preconditioning, unlike older agents 1

Dosing Strategy

• Start at low doses and gradually increase to avoid hypoglycemia 1
• When symptoms are marked, maximum doses can quickly distinguish patients who need insulin from those who will respond to oral therapy 7

Monitoring Requirements

• Increased vigilance for hypoglycemia is required, particularly in elderly patients who have relatively higher risk of severe episodes 1
• Self-monitoring of blood glucose may be unnecessary when using metformin combined with SGLT-2 inhibitors or GLP-1 agonists, but remains important with sulfonylureas due to hypoglycemia risk 1

Critical Pitfalls to Avoid

Inappropriate Continuation

• Do not continue maximum doses of sulfonylureas in poorly controlled patients—this represents misuse of the medication 7
• Patients with inadequate control on maximum sulfonylurea doses should be transitioned to insulin or have newer agents added, not maintained on ineffective therapy 7

Combination Therapy Errors

• When adding SGLT-2 inhibitors or GLP-1 agonists achieves adequate control, reduce or discontinue sulfonylureas to minimize hypoglycemia risk 1
• Avoid combining sulfonylureas with ineffective insulin doses; instead, discontinue the sulfonylurea and increase insulin appropriately 7

Patient Selection Errors

• Do not use sulfonylureas in type 1 diabetes (completely ineffective) or in type 2 diabetes patients who respond satisfactorily to diet alone (unnecessary) 7
• Exercise caution in elderly patients due to increased hypoglycemia risk 1

Contemporary Treatment Paradigm

The evidence strongly supports prioritizing SGLT-2 inhibitors and GLP-1 agonists over sulfonylureas for most patients with type 2 diabetes requiring treatment intensification beyond metformin 1. Sulfonylureas retain value primarily in resource-limited settings, specific monogenic diabetes subtypes, and situations where newer agents are contraindicated or unaffordable 1, 5. When sulfonylureas are used, select second-generation agents, start at low doses, monitor closely for hypoglycemia, and transition to more effective therapies if glycemic targets are not achieved 1.