Do sodium‑glucose co‑transporter‑2 (SGLT2) inhibitors improve insulin sensitivity in an adult with type 2 diabetes who is not at glycemic target on metformin?

Do SGLT2 Inhibitors Improve Insulin Sensitivity?

SGLT2 inhibitors do improve insulin sensitivity indirectly through reduction of glucotoxicity, but this is a secondary metabolic effect rather than their primary mechanism of action. 1, 2

Primary Mechanism: Insulin-Independent Glucose Lowering

SGLT2 inhibitors work by blocking glucose reabsorption in the proximal renal tubule, promoting urinary glucose excretion independently of insulin signaling. 3 This insulin-independent mechanism distinguishes them from most other diabetes medications and allows them to function regardless of β-cell function or insulin resistance severity. 4, 5

Secondary Effect: Improvement in Insulin Sensitivity

Reduction of Glucotoxicity

By lowering chronic hyperglycemia through sustained glucose excretion, SGLT2 inhibitors reduce glucotoxicity, which subsequently improves both β-cell function and peripheral tissue insulin sensitivity. 1, 6 This represents an indirect insulin-sparing effect that gradually enhances insulin sensitivity over time. 2

The mechanism operates through:

• Improved β-cell function by reducing the toxic effects of chronic hyperglycemia on pancreatic β-cells 6, 4
• Enhanced peripheral insulin sensitivity as glucose toxicity diminishes 1, 2
• Reduced insulin resistance through metabolic improvements secondary to glucose unloading 6

Clinical Evidence

Studies demonstrate that SGLT2 inhibitors improve insulin resistance and increase insulin sensitivity in patients with type 2 diabetes, though the magnitude of this effect varies. 2, 5 The improvement in insulin sensitivity is most pronounced when baseline glucotoxicity is severe, as the reduction in chronic hyperglycemia allows recovery of insulin signaling pathways. 1

Compensatory Mechanisms That May Limit Benefits

A critical caveat: SGLT2 inhibitors trigger compensatory increases in endogenous glucose production, likely driven by increased glucagon secretion, which may somewhat attenuate both the glucose-lowering effect and improvements in insulin sensitivity. 1 This represents an important limitation of the insulin-sensitizing effect.

Clinical Implications for Your Patient

For an adult with type 2 diabetes not at glycemic target on metformin:

• SGLT2 inhibitors will provide insulin-independent glucose lowering as their primary benefit, with modest improvements in insulin sensitivity as a secondary effect 3
• The combination of metformin (which reduces hepatic glucose output) with an SGLT2 inhibitor is particularly appealing because metformin may dampen the compensatory increase in glucagon-driven glucose production 1
• Prioritize SGLT2 inhibitors for patients with established cardiovascular disease or chronic kidney disease, where they reduce all-cause mortality, major adverse cardiovascular events, CKD progression, and heart failure hospitalizations (high certainty of evidence) 3
• Do not select SGLT2 inhibitors primarily for insulin sensitization—if improving insulin sensitivity is the primary goal, consider GLP-1 receptor agonists or thiazolidinediones instead 3

Common Pitfalls to Avoid

• Do not expect SGLT2 inhibitors to function like thiazolidinediones (which directly improve insulin sensitivity through PPAR-γ activation)—the insulin-sensitizing effect of SGLT2 inhibitors is indirect and secondary to glucotoxicity reduction 1, 2
• Do not overlook the proven cardiovascular and renal benefits when making treatment decisions, as these outcomes (mortality, MACE, CKD progression) are more clinically significant than modest improvements in insulin sensitivity 3
• Be aware that glucose-lowering efficacy progressively declines as eGFR falls below 45 mL/min/1.73 m², though cardiorenal benefits persist even when glycemic effects are minimal 7