What guidelines state that nateglinide and sulfonylureas (SUs) are not recommended as first-line treatments for type 2 diabetes mellitus (T2DM)?

Guidelines on Nateglinide and Sulfonylureas in Type 2 Diabetes Management

Current guidelines recommend against using nateglinide and sulfonylureas as first-line treatments for type 2 diabetes due to their inferior cardiovascular outcomes, higher hypoglycemia risk, and the availability of superior alternatives like SGLT-2 inhibitors and GLP-1 receptor agonists. 1

Guideline Recommendations Against Sulfonylureas and Nateglinide

American College of Physicians (ACP) Guidelines

The 2024 ACP visual clinical guideline explicitly states that "sulfonylureas and long-acting insulins are inferior to SGLT-2 inhibitors and GLP-1 agonists in reducing all-cause mortality and morbidity" 1. The guideline recommends reducing or discontinuing sulfonylureas when adding an SGLT-2 inhibitor or GLP-1 agonist due to increased risk for severe hypoglycemia.

American Heart Association (AHA)

The AHA's 2020 scientific statement on management of stable coronary artery disease in patients with T2DM clearly states that "neither insulin nor sulfonylureas should be first-line therapies for most patients with established CAD" 1. This recommendation is based on concerns about hypoglycemia risk and the cardiovascular benefits associated with newer glucose-lowering drugs.

American Diabetes Association (ADA)

The ADA's 2025 Standards of Care for Older Adults specifically cautions against sulfonylureas and meglitinides (including nateglinide):

• "Sulfonylureas and other insulin secretagogues such as the meglitinides (repaglinide and nateglinide) are associated with hypoglycemia, bone loss, and fracture risk and should be used with caution" 1

Pregnancy-Specific Guidelines

For gestational diabetes, the ADA's 2023 Standards of Care in Diabetes Pregnancy states that glyburide (a sulfonylurea) "failed to be found noninferior to insulin" and notes concerns about neonatal hypoglycemia, macrosomia, and lack of long-term safety data for offspring 1.

Reasons for Not Recommending These Medications

1. Hypoglycemia Risk

• Sulfonylureas and nateglinide significantly increase the risk of hypoglycemia compared to newer agents 1
• This risk is particularly problematic in older adults, who are more vulnerable to adverse outcomes from hypoglycemic episodes 1

2. Cardiovascular Outcomes

• Newer medications (SGLT-2 inhibitors and GLP-1 agonists) have demonstrated superior cardiovascular outcomes 1
• Sulfonylureas have been associated with increased cardiovascular mortality in retrospective observational studies 1

3. Weight Effects

• Unlike GLP-1 agonists which promote weight loss, sulfonylureas and nateglinide can cause weight gain 1

4. Bone Health Concerns

• These medications are associated with bone loss and increased fracture risk 1

Special Populations Where Caution Is Particularly Warranted

Older Adults

• The ADA specifically recommends caution with sulfonylureas and meglitinides in older adults 1
• If sulfonylureas must be used in older adults, shorter-acting agents like glipizide are preferred over longer-acting ones like glyburide 1

Patients with Cardiovascular Disease

• The AHA recommends against using sulfonylureas as first-line therapy in patients with established coronary artery disease 1

Pregnant Women

• Sulfonylureas are associated with increased neonatal hypoglycemia and macrosomia in gestational diabetes 1

Current Preferred First-Line Treatments

According to the most recent guidelines, preferred treatments include:

1. Metformin - Still considered the cornerstone of initial therapy for most patients
2. SGLT-2 inhibitors - Particularly beneficial for patients with heart failure or chronic kidney disease
3. GLP-1 receptor agonists - Especially valuable for patients with high cardiovascular risk or when weight loss is desired

Conclusion

Multiple current guidelines from major medical organizations (ACP, AHA, ADA) recommend against using nateglinide and sulfonylureas as first-line treatments for type 2 diabetes. These recommendations are based on their inferior cardiovascular outcomes, higher hypoglycemia risk, and the availability of superior alternatives with better safety profiles and additional benefits beyond glycemic control.