What is the role of sulfonylureas (SUs) in treating type 2 diabetes mellitus (T2DM)?

Sulfonylureas in Type 2 Diabetes Management

Sulfonylureas should not be used as first-line therapy and are increasingly relegated to a limited role as second-line agents, primarily in resource-constrained settings where cost is prohibitive for newer medications, but they are inferior to SGLT-2 inhibitors and GLP-1 agonists for reducing mortality and morbidity. 1

Current Position in Treatment Algorithms

First-Line Therapy

• Metformin remains the recommended first-line pharmacologic therapy for type 2 diabetes in the absence of contraindications 1
• Sulfonylureas are not recommended as initial monotherapy given their association with increased all-cause mortality (additional 21.4 deaths per 1,000 patients per year), cardiovascular death (additional 3.5 deaths per 1,000 patients per year), and ischemic stroke (additional 2.0 strokes per 1,000 patients per year) compared to metformin 2

Second-Line Therapy Hierarchy

When metformin alone fails to achieve glycemic control, the treatment hierarchy is:

1. Preferred agents (in patients with established cardiovascular disease, heart failure, or chronic kidney disease):

   • SGLT-2 inhibitors for patients with heart failure or CKD 1, 3
   • GLP-1 receptor agonists for patients with increased stroke risk or when weight loss is a treatment goal 1, 3

2. Alternative agents (when preferred agents are unsuitable or cost-prohibitive):

   • Sulfonylureas may be considered in resource-limited settings 1, 4
   • WHO guidelines give sulfonylureas a strong recommendation as second-line treatment specifically for low-resource settings 1

3. When to deprioritize sulfonylureas:

   • The American College of Physicians states that sulfonylureas are inferior to SGLT-2 inhibitors and GLP-1 agonists in reducing all-cause mortality and morbidity 1
   • Current ADA/EASD guidelines no longer position sulfonylureas as preferred second-line agents after metformin 3

Efficacy Profile

Glycemic Control

• Sulfonylureas reduce HbA1c by 1.0-1.5% from baseline 1
• They demonstrate similar glucose-lowering efficacy to metformin and other second-line agents 1
• DPP-4 inhibitors show slightly less glucose-lowering effect, increasing HbA1c by 0.12% compared to sulfonylureas 1

Durability Concerns

• Sulfonylureas lack durable effect on glucose lowering over time, which is particularly problematic in long-standing diabetes where β-cell function is already compromised 3
• This progressive loss of efficacy requires dose escalation or addition of other agents more rapidly than with newer medications 3

Safety Considerations and Major Adverse Effects

Hypoglycemia Risk (Most Critical Safety Concern)

Severe hypoglycemia rates:

• Sulfonylureas carry significantly higher hypoglycemia risk compared to DPP-4 inhibitors (OR 0.14) and SGLT-2 inhibitors (OR 0.09) 1
• Risk is particularly elevated in elderly patients, those with chronic kidney disease, and patients with renal impairment 1, 3

Clinical consequences of hypoglycemia:

• Falls, injuries, fractures, motor vehicle accidents, and potentially fatal cardiac arrhythmias 3
• Prolonged and life-threatening episodes can occur, though severe episodes requiring assistance, coma, or seizure are infrequent 1

Risk mitigation strategies:

• Use newer-generation sulfonylureas (glimepiride, gliclazide, glipizide) which have lower hypoglycemia risk than first-generation agents like chlorpropamide and glyburide 1, 3
• Avoid glyburide entirely due to substantially greater hypoglycemia risk 1
• When adding SGLT-2 inhibitors or GLP-1 agonists to achieve adequate glycemic control, reduce or discontinue sulfonylureas due to increased severe hypoglycemia risk 1

Cardiovascular Safety

Mortality concerns:

• Sulfonylureas are not associated with increased mortality in patients with established heart failure based on observational studies of >16,000 Medicare recipients 1
• However, some observational studies suggest improved survival with metformin compared to sulfonylureas 1

Cardiovascular outcomes:

• The CAROLINA trial showed no difference in cardiovascular outcomes between glimepiride and linagliptin, though sulfonylureas had higher hypoglycemia rates 3
• Recent systematic reviews found no increase in all-cause mortality compared with other active treatments 3
• Older-generation sulfonylureas may impair cardiac ischemic preconditioning through nonselective effects on cardiac K-ATPase channels, but this does not appear to occur with newer-generation agents 1

Weight Gain

• Weight gain of approximately 2 kg is common following initiation of sulfonylurea therapy 1
• This is relatively modest in large cohort studies but may be detrimental in long-standing diabetes where obesity is often a comorbidity 3
• In contrast, both DPP-4 inhibitors and SGLT-2 inhibitors promote weight loss 1

Special Populations and Clinical Contexts

Heart Failure Patients

• Sulfonylureas are commonly used in diabetic patients with heart failure (approximately half of >16,000 Medicare HF patients were treated with sulfonylureas) 1
• They were not associated with increased mortality in this population 1
• Important adverse effects in HF patients include hypoglycemia risk and weight gain 1

Renal Impairment

• Patients with mild renal insufficiency should use gliquidone specifically 1
• Sulfonylureas are contraindicated in significant renal dysfunction due to prolonged hypoglycemia risk 1
• Dose adjustments are necessary based on kidney function 3

Hospital/Inpatient Setting

• Professional societies recommend against the use of sulfonylureas in the hospital because of potential risk of sustained hypoglycemia 1
• Retrospective reports show that patients treated with sulfonylureas might develop at least one episode of hypoglycemia in the hospital, with risk associated with older age, concurrent insulin treatment, and renal impairment 1
• Exception: UK recommendations suggest sulfonylureas might be useful in managing glucocorticoid-induced hyperglycemia 1

Elderly Patients

• Severe hypoglycemic episodes are relatively more frequent in elderly patients 1
• Elderly patients or those with chronic kidney disease require particular caution due to increased hypoglycemia risk 3

Cost Considerations and Resource-Limited Settings

When sulfonylureas remain appropriate:

• Patients for whom cost is a significant barrier to medication adherence are suitable candidates 3
• Sulfonylureas are inexpensive and widely available, with favorable cost profiles compared to newer agents 3, 4
• In resource-constrained settings, routine utilization of sulfonylureas as second-line agents continues to be acceptable 4
• WHO specifically recommends sulfonylureas for low-resource settings where newer agents cost several times more than human insulin 1

Cost-benefit analysis:

• While newer agents (SGLT-2 inhibitors, GLP-1 agonists) have no generic formulations currently available, clinicians should prescribe generic medications when they become available 1
• Prevention of long-term complications will likely reduce long-term expenses attributed to the disease, potentially offsetting higher upfront medication costs 1

Practical Algorithm for Sulfonylurea Use

Step 1: Determine if sulfonylureas should be considered at all

• ❌ Do NOT use if patient has established cardiovascular disease, heart failure, or CKD → use SGLT-2 inhibitors or GLP-1 agonists instead 1, 3
• ❌ Do NOT use as first-line therapy → use metformin 1
• ❌ Do NOT use in hospitalized patients (except for glucocorticoid-induced hyperglycemia) 1
• ✓ Consider only if cost is prohibitive for newer agents AND patient lacks cardiovascular/renal comorbidities 3, 4

Step 2: If sulfonylureas are appropriate, select the safest agent

• ✓ Use: Glimepiride, gliclazide, or glipizide (newer-generation agents with lower hypoglycemia risk) 1, 3
• ❌ Avoid: Glyburide/glibenclamide and chlorpropamide (substantially greater hypoglycemia risk) 1

Step 3: Assess hypoglycemia risk factors

• High-risk patients requiring extra caution: elderly, chronic kidney disease, renal impairment, concurrent insulin use 1, 3
• Monitor for hypoglycemia, especially in high-risk patients 3

Step 4: Plan for transition when circumstances change

• When adding SGLT-2 inhibitors or GLP-1 agonists for cardiovascular/renal protection, reduce or discontinue sulfonylureas 1
• Recognize that sulfonylureas lack durability and will likely require intensification over time 3

Mechanism and Pharmacology

• Sulfonylureas lower blood glucose by stimulating insulin release from pancreatic β-cells through closure of ATP-sensitive potassium channels 5
• Time to maximal effect (minimum blood glucose) is approximately 2-3 hours after single oral doses 5
• Glimepiride demonstrates linear pharmacokinetics across the 1-8 mg dose range, with peak concentrations 2-3 hours post-dose 5
• When given with meals, glimepiride Cmax and AUC decrease by only 8% and 9% respectively, allowing flexible dosing 5

Common Pitfalls to Avoid

1. Using sulfonylureas when newer agents would provide mortality/morbidity benefit: In patients with established cardiovascular disease or at very high cardiovascular risk, SGLT-2 inhibitors and/or GLP-1 agonists should be used as part of diabetes management, as using sulfonylureas may deprive patients of key cardiorenal benefits 4, 3

2. Selecting high-risk sulfonylureas: Always avoid glyburide/glibenclamide due to substantially greater hypoglycemia risk 1

3. Continuing sulfonylureas when adding cardioprotective agents: When SGLT-2 inhibitors or GLP-1 agonists are added and achieve adequate glycemic control, sulfonylureas should be reduced or discontinued to minimize hypoglycemia risk 1

4. Using sulfonylureas in hospitalized patients: Professional societies recommend against this practice due to sustained hypoglycemia risk 1

5. Ignoring renal function: Dose adjustments or agent selection (gliquidone for mild renal insufficiency) are essential 1