Clinical bottom line
Selective sodium-glucose cotransporter 1 (SGLT1) inhibitors represent a novel class of oral agents under investigation for heart failure management. Early evidence suggests potential cardiovascular benefits distinct from the well-established effects of SGLT2 inhibitors, possibly through modulation of intestinal glucose absorption and myocardial metabolism. However, clinical data remain limited, and the impact of selective SGLT1 inhibition on heart failure outcomes is currently hypothesis-generating and warrants further rigorous evaluation before routine clinical adoption.
What the evidence shows
Sodium-glucose cotransporter proteins facilitate renal and intestinal glucose reabsorption, with SGLT2 inhibitors already established as effective therapies in heart failure with reduced and preserved ejection fraction (Mukesh et al., 2025). In contrast, selective SGLT1 inhibitors target primarily intestinal glucose absorption and may influence cardiac metabolism indirectly, offering a complementary or alternative mechanism to SGLT2 inhibition.
Preclinical and early-phase clinical studies have explored the cardiovascular effects of SGLT1 inhibition, highlighting potential benefits including improved glycemic control, reduced postprandial glucose excursions, and modulation of myocardial energy substrate utilization. These effects could translate into improved cardiac function and reduced heart failure progression, especially in patients with concomitant diabetes or impaired glucose metabolism.
However, the bulk of robust clinical evidence remains focused on SGLT2 inhibitors, with comprehensive systematic reviews detailing their impact on heart failure outcomes [1,2]. These reviews underscore significant reductions in hospitalization and mortality with SGLT2 inhibition but do not extend these findings to selective SGLT1 inhibitors, which have not yet been evaluated in large-scale randomized controlled trials.
Caveats and uncertainty
The current understanding of selective SGLT1 inhibitors in heart failure is limited by a paucity of large, well-powered clinical trials. Most available data derive from preclinical models or early-phase human studies primarily focused on metabolic endpoints rather than hard cardiovascular outcomes. Thus, the cardiovascular safety profile, optimal patient populations, and comparative efficacy relative to SGLT2 inhibitors remain undefined.
Moreover, the dual inhibition of SGLT1 and SGLT2 has been explored in some agents, complicating the attribution of observed effects solely to SGLT1 inhibition. Potential gastrointestinal adverse effects due to intestinal glucose malabsorption also require careful assessment in clinical contexts.
Given these uncertainties, selective SGLT1 inhibitors should be considered investigational in heart failure management until further evidence clarifies their role.
How this may change practice
If ongoing and future trials demonstrate that selective SGLT1 inhibitors confer cardiovascular benefits comparable or complementary to SGLT2 inhibitors, they could expand therapeutic options for heart failure, particularly in patients with diabetes or those intolerant to SGLT2 inhibitors. Their distinct mechanism may also offer additive benefits when combined with existing therapies.
Clinicians should remain attentive to emerging data but continue to rely on established evidence-based therapies, including SGLT2 inhibitors, for heart failure management. Participation in clinical trials evaluating selective SGLT1 inhibitors may be appropriate in specialized settings.