What are the downsides to using sulfonylureas (e.g. glyburide, glipizide) in patients with type 2 diabetes, particularly those with a history of cardiovascular disease or impaired renal function?

Downsides to Sulfonylureas in Type 2 Diabetes

Sulfonylureas carry significant risks of hypoglycemia, weight gain, and potential cardiovascular mortality, with professional societies recommending against their routine hospital use and advising caution in patients with cardiovascular disease, renal impairment, or advanced age. 1

Primary Safety Concerns

Hypoglycemia Risk

• All sulfonylureas are capable of producing severe, sustained hypoglycemia, which represents the most clinically significant adverse effect affecting morbidity and mortality. 1, 2, 3
• Risk is substantially elevated in elderly patients, those with renal impairment, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency. 2, 3
• Patients treated with sulfonylureas may develop at least one episode of hypoglycemia in the hospital, with risk associated with older age, concurrent insulin treatment, and renal impairment. 1
• Hypoglycemia may be difficult to recognize in elderly patients and those taking beta-adrenergic blocking drugs. 2, 3

Critical distinction between agents: Nonspecific, long-acting sulfonylureas (glyburide and glimepiride) have a 2.83-fold increased risk of severe hypoglycemia compared to specific, short-acting agents (gliclazide, glipizide, tolbutamide). 4 Glyburide has the highest frequency of hypoglycemia among all sulfonylureas and should be avoided entirely in elderly patients. 1

Weight Gain

• Weight gain of approximately 2 kg is common following sulfonylurea initiation, though this is relatively modest compared to insulin or thiazolidinediones. 1
• This weight gain represents an important adverse effect relevant to patients with heart failure and contributes to insulin resistance. 1

Cardiovascular and Mortality Concerns

Increased Mortality Risk

Initiating treatment with a sulfonylurea rather than metformin is associated with significantly higher mortality rates. 5 Specifically:

• 25% increased risk of ischemic stroke (HR 1.25,95% CI 1.002-1.56) 5
• 25% increased risk of cardiovascular death (HR 1.25,95% CI 1.06-1.47) 5
• 60% increased risk of all-cause mortality (HR 1.60,95% CI 1.45-1.76) 5

This translates to an additional 2.0 ischemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year compared to metformin. 5

Cardiovascular Disease Considerations

• Neither insulin nor sulfonylureas should be first-line therapies for most patients with established coronary artery disease, given the documented cardiovascular benefits of newer agents like SGLT2 inhibitors and GLP-1 receptor agonists. 1
• Older-generation sulfonylureas may impair cardiac ischemic preconditioning through nonselective effects on pancreatic and cardiac K-ATPase channels, though this does not appear to occur with newer-generation agents. 1
• Observational studies suggest improved survival with metformin compared with sulfonylurea therapy in patients with heart failure. 1

Renal Impairment Complications

Accumulation and Prolonged Effects

• Renal or hepatic insufficiency causes elevated drug levels and diminished gluconeogenic capacity, both increasing the risk of serious hypoglycemic reactions. 2, 3
• Progressive kidney function decline increases hypoglycemia risk with all sulfonylureas due to decreased drug clearance and impaired renal gluconeogenesis. 6
• Metformin dose reduction is recommended if eGFR is 30-45 mL/min per 1.73 m²; metformin should be discontinued if eGFR is less than 30 mL/min per 1.73 m². 1

Agent-Specific Recommendations

Glipizide is the only sulfonylurea recommended in renal impairment because it lacks active metabolites that accumulate, though conservative initiation at 2.5 mg once daily and slow titration remain necessary. 7, 6 Glyburide is explicitly contraindicated in patients with chronic kidney disease. 7

Hospital Setting Risks

• Professional societies recommend against the use of sulfonylureas in the hospital because of the potential risk of sustained hypoglycemia. 1
• An exception exists for UK recommendations suggesting sulfonylureas might be useful in managing glucocorticoid-induced hyperglycemia. 1
• Sulfonylureas should be discontinued in patients at risk for lactic acidosis (acute kidney injury, hypoxia, shock) or before iodinated contrast imaging procedures in high-risk patients. 1

Secondary Failure and Loss of Efficacy

• The effectiveness of sulfonylureas in lowering blood glucose decreases in many patients over time, which may be due to progression of diabetes severity or diminished drug responsiveness. 2, 3
• This phenomenon, known as secondary failure, results from progressive reduction in insulin-producing capacity by pancreatic beta cells and is also seen with other antihyperglycemic agents. 8

Drug Interactions and Special Warnings

Hemolytic Anemia Risk

• Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylureas can lead to hemolytic anemia; a non-sulfonylurea alternative should be considered. 2, 3
• Hemolytic anemia has also been reported in patients without known G6PD deficiency. 2, 3

Medication Interactions

• Antimicrobials (fluoroquinolones and sulfamethoxazole-trimethoprim) interact with sulfonylureas to increase effective dose and may precipitate hypoglycemia; temporary dose reduction or discontinuation should be considered. 7
• DPP-4 inhibitors increase hypoglycemia risk by approximately 50% when combined with sulfonylureas compared to DPP-4 inhibitor monotherapy. 7, 6
• GLP-1 receptor agonists increase hypoglycemic potential when combined with sulfonylureas. 7, 6

Lack of Cardiovascular Benefit

• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide, glipizide, or any other sulfonylurea. 2, 3
• In contrast, SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiovascular and renal benefits in patients with established cardiovascular disease, heart failure, or chronic kidney disease. 1, 9

Common Clinical Pitfalls to Avoid

1. Never use glyburide in elderly patients or those with any degree of renal impairment due to prolonged hypoglycemia risk. 1, 7

2. Avoid combining sulfonylureas with insulin without reducing the sulfonylurea dose by at least 50% or discontinuing entirely to prevent severe hypoglycemia. 7

3. Do not use sulfonylureas as first-line therapy in patients with established cardiovascular disease, heart failure, or chronic kidney disease when SGLT2 inhibitors or GLP-1 receptor agonists are available. 1, 9

4. Discontinue sulfonylureas during acute illness, procedures with iodinated contrast, or when prescribing interacting antimicrobials. 7

5. Recognize that hypoglycemia may be difficult to detect in elderly patients and those on beta-blockers, requiring enhanced monitoring. 2, 3

Contemporary Context

While sulfonylureas remain acceptable second-line agents primarily when cost is an important consideration (they are inexpensive and reduce HbA1c by approximately 1.5 percentage points), their routine use may deprive patients of key advantages and potentially important cardiorenal benefits offered by newer agents. 9 In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT2 inhibitors and/or GLP-1 receptor agonists should be used as part of diabetes management in the absence of contraindications. 9