What is the mechanism by which ertugliflozin (SGLT2 inhibitor) leads to elevated triglycerides?

Mechanism of Ertugliflozin-Induced Elevated Triglycerides

The primary mechanism by which ertugliflozin leads to elevated triglycerides is through metabolic substrate shifting, where inhibition of renal glucose reabsorption promotes lipolysis and increases hepatic very-low-density lipoprotein (VLDL) production, resulting in higher circulating triglyceride levels.

Metabolic Pathway Changes

• SGLT2 inhibitors like ertugliflozin block glucose reabsorption in the proximal renal tubules, causing increased urinary glucose excretion and creating a state of relative carbohydrate deprivation 1
• This carbohydrate deprivation triggers compensatory metabolic shifts toward increased fat mobilization and utilization 2
• The resulting increase in free fatty acid (FFA) flux to the liver drives increased hepatic VLDL production and secretion, leading to elevated triglyceride levels 3

Specific Lipid Metabolism Effects

• Ertugliflozin treatment diverts metabolism toward lipolysis, β-oxidation, and ketogenesis, which can increase circulating triglyceride levels as part of this metabolic adaptation 2
• Studies have shown that SGLT2 inhibition increases the percentage of very-low-density lipoprotein (VLDL) while decreasing the percentage of high-density lipoprotein (HDL) as a proportion of total serum lipids 4
• This lipid profile shift results from altered hepatic lipid metabolism in response to the drug's primary mechanism of action 5

Clinical Evidence

• Research has demonstrated that SGLT2 inhibitor treatment can increase triglyceride levels from baseline median values of 0.5 mmol/L to 1.0 mmol/L after 30 days of treatment 4
• In some cases, significant hypertriglyceridemia (>2.0 mmol/L) has been observed in approximately 21% of subjects receiving SGLT2 inhibitors 4
• This effect appears to be a class effect of SGLT2 inhibitors rather than specific to ertugliflozin alone 6

Physiological Context

• Under normal conditions, insulin suppresses adipocyte lipolysis and promotes degradation of newly synthesized apolipoprotein B in the liver 3
• SGLT2 inhibition creates a state that mimics aspects of insulin deficiency, with increased adipocyte lipolysis and FFA mobilization driving hepatic VLDL apolipoprotein B secretion 3
• The metabolic adaptation to SGLT2 inhibition includes shifts in myocardial metabolism away from glucose oxidation toward ketone bodies, which may contribute to the observed lipid profile changes 3

Clinical Implications

• While elevated triglycerides are a potential side effect of ertugliflozin therapy, this must be balanced against the significant cardiovascular and renal benefits of SGLT2 inhibitors 3
• Monitoring of lipid profiles is advisable in patients treated with ertugliflozin, particularly in those with pre-existing dyslipidemia 5
• The triglyceride elevation effect appears to be more pronounced in individuals with higher baseline insulin levels and pre-existing abnormalities in lipid metabolism 4

Caveat

• Most human studies have focused on the cardiovascular and glycemic benefits of SGLT2 inhibitors rather than specifically investigating their effects on triglyceride metabolism 3
• The clinical significance of ertugliflozin-induced triglyceride elevation remains uncertain, particularly regarding its impact on cardiovascular risk in the context of the drug's overall cardioprotective effects 3